Tricyclic derivatives and their pharmaceutical use and compositions

ABSTRACT

This application relates to tricyclic compounds of Formula I: 
                         
including all stereoisomers, mixtures of stereoisomers, and salts thereof. This application also relates to compositions comprising compounds of Formula I and uses therefore.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No. PCT/US2010/060937, filed Dec. 17, 2010, which claims priority to U.S. Provisional Application Ser. No. 61/289,090, filed Dec. 22, 2009. The disclosures of the aforementioned applications are incorporated herein by reference in their entireties for all purposes.

SUMMARY

This application relates to tricyclic compounds of Formula I:

including all stereoisomeric forms and all mixtures of stereoisomeric forms of these compounds.

This application also relates to salts of the compounds of Formula I and compositions comprising compounds of Formula I or salts of compounds of Formula I.

This application further relates to pharmaceutically acceptable salts of the compounds of Formula I and pharmaceutical compositions comprising compounds of Formula I or pharmaceutically acceptable salts of the compounds of Formula I.

The compounds of Formula I and/or their pharmaceutically acceptable salts are useful for treating conditions, disorders and diseases mediated by one or more members of the serotonin receptor (5-HT) family, such as for example, 5-HT₆ and 5-HT₇ receptors.

Compounds of Formula I are 5-HT₆ receptor ligands and are therefore useful in the treatment of various conditions, disorders or diseases such as those related to the central nervous system (CNS) and the gastrointestinal (GI) tract.

It should be understood that the section titles used in this application are for indexing and search purposes only and should not be construed as limiting in any way.

BACKGROUND

Serotonin has been implicated in a number of conditions, disorders and diseases that originate in the central nervous system. These include conditions, disorders and diseases related to mood, cognitive function, sleeping, eating, pain, depression, anxiety, schizophrenia, and other bodily states. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.

The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT₁-5-HT₇) encompassing 14 human subclasses which modulate the effects of the neurotransmitter 5-hydroxytryptamine (5-HT, serotonin). The 5-HT₆ receptor is the latest serotonin receptor to be identified by molecular cloning both in rats and in humans. Mol. Pharmacol. 1993, 43, 320-327; J Neurochem, 1996, 66, 47-56. The human 5-HT₆ receptor is a 440 amino acid polypeptide with seven transmembrane spanning domains which is consistent with the structure of a G protein-coupled receptor (GPCR). There is about 89% sequence homology between 5-HT₆ receptors in human and rat and the relative distribution of 5-HT₆ receptor mRNA in the brain also appears to be similar. Together, these observations suggest that the rat is an appropriate model for predicting the pharmacology of 5-HT₆ receptor ligands in humans.

The 5-HT₆ receptor is primarily present in the central nervous system and is involved in glutamatergic and cholinergic neuronal activity. Curr Drug Targets CNS Neurol Disord, 2004, 3, 59-79. Blocking the function of 5-HT₆ receptors has been found to increase acetylcholine (ACh) and glutamate-mediated neurotransmission, and enhance cognitive processes. Several antidepressants and atypical antipsychotics have also been shown to bind to the 5-HT₆ receptor with high affinity. This binding may be a contributing factor in the therapeutic profile of these drugs. 5-HT₆ receptor activity has also been linked to generalized states of stress and anxiety. Life Sciences, 1998, 62, 1473-1477. Taken together, these studies and observations suggest that compounds with 5-HT₆ receptor affinity may be useful for the treatment of various conditions, disorders or diseases related to the central nervous system (CNS) such as cognitive diseases, neurodegenerative diseases, schizophrenia, anxiety, and depression. Other CNS-related conditions, disorders or diseases that may be affected by modulating 5-HT₆ receptor activity include sleep/wakefulness disorders as well as nociception, i.e., the neural processes of encoding and processing noxious stimuli.

The 5-HT₆ receptor has also been shown to play a role in conditions, disorders or diseases that relate to food ingestion or food intake, such as, for example, anorexia, cachexia, and obesity. See, for example, Drug Discovery Today, 2006, 11, 283-299. The 5-HT₆ receptor is also thought to be involved in conditions, disorders or diseases related to the gastrointestinal (GI) tract, such as irritable bowel syndrome and functional bowel disorder.

Given the broad spectrum of physiologic effects that are mediated by serotonin there is a tremendous amount of interest in identifying and developing compounds that affect serotonergic systems, including those conditions, disorders or diseases that are directly or indirectly mediated, effected, controlled, or influenced by the 5-HT₆ receptor. Compounds that have affinity for, interact with, stimulate, or inhibit the 5-HT₆ receptor are commonly referred to as 5-HT₆ ligands.

This application relates to new compounds with affinity for the 5-HT₆ receptor, i.e., 5-HT₆ ligands, which may be useful as active ingredients in pharmaceutical preparations for the treatment of certain conditions, disorders or diseases related to the central nervous system (CNS) such as memory disorders, anxiety, epilepsy, migraine, panic attacks, depression, bipolar disorder, obsessive compulsive disorders, cognition/cognitive disorders, mild cognitive impairment (MCl), senile dementia, psychosis, schizophrenia, ADHD/ADD; or for the treatment of pain including neuropathic pain and chronic pain; head trauma or injury; or for the treatment of neurodegenerative conditions, disorders or diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis; or for the treatment of conditions, disorders or diseases related to addiction and/or withdrawal from substances such as narcotics, ethanol (alcoholism), nicotine, and/or benzodiazepines; sleep/wakefulness disorders; or for the treatment of gastrointestinal (GI) conditions, disorders or diseases such as irritable bowel syndrome (IBS), functional bowel disorder; or for the treatment of conditions, disorders or diseases related to feeding behaviors or food intake such as anorexia, cachexia, and obesity.

These compounds may also be useful for the improvement of cognition (cognitive enhancement) and/or improvement of memory in otherwise healthy subjects.

DETAILED DESCRIPTION

The following provides additional non-limiting details of the compounds of Formula I, compounds of Formulae II through V, as well as various species and more specific embodiments of the same, intermediates, and other compounds of interest.

As used herein, the term “compound(s) of Formula I” should be understood as including compounds of Formulae II through V, unless expressly stated to the contrary.

As used herein, the term “compound(s)” whether used by itself or in combination with any Formula should be understood as including all stereoisomers, all mixtures of stereoisomers, and all salts of such compounds, stereoisomers, and mixtures of stereoisomers, unless expressly stated to the contrary. Accordingly, use of the phrase “compound(s) of Formula I or salts thereof” refers to and includes compounds of Formulae I through Formula V, all stereoisomers, all mixtures of stereoisomers, and all salts of such compounds, stereoisomers, and mixtures of stereoisomers. This understanding extends to pharmaceutical compositions and methods that employ or comprise one or more compounds of Formula I.

One aspect of this application is directed to compounds of Formula I

or salts thereof wherein:

X is selected from S, O, or NH;

A is —(CR⁹R¹⁰)_(n)— and n is 1, 2, or 3 and R⁹ and R¹⁰ at each occurrence are each independently selected from H or unsubstituted (C₁-C₆)alkyl, or (C₁-C₆)haloalkyl;

R¹ at each occurrence is independently selected from H, halogen, CN, NO₂, NR¹¹R¹², COR¹³, CO₂R¹³, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)haloalkoxy, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and W is 0, 1, 2 or 3, wherein any of the foregoing, except for H, halogen, CN, and NO₂, is optionally substituted with one or more substituents;

R² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, CO(C₁-C₆)alkyl, CO₂(C₁-C₆)alkyl, CO(C₆-C₁₀)aryl, CO₂(C₆-C₁₀)aryl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, CO(C₃-C₁₀)cycloalkyl, CO₂(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, CO(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, CO₂(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, CO(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, CO₂(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, CO(C₅-C₉)heteroaryl, CO₂(C₅-C₉)heteroaryl, (C₁-C₆)alkyl(C₅-C₉)heteroaryl, CO(C₁-C₆)alkyl(C₅-C₉)heteroaryl, and CO₂(C₁-C₆)alkyl(C₅-C₉)heteroaryl, wherein any of the foregoing, except for H, is optionally substituted with one or more substituents;

R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)aminoalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-CON(R¹³)₂, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryloxy, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyloxy, (C₅-C₉)heteroaryl, (C₅-C₉)heteroaryloxy, (C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryloxy, wherein any of the foregoing, except for H, is optionally substituted with one or more substituents; or

R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the foregoing is optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)hydroxyalkyl, COR¹¹, CO₂R¹¹, CONR¹¹R¹³, halogen, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, OR¹³, and oxo; or

R² and one of R³ or R⁴ are taken together to form an optionally substituted (C₃-C₉)heterocycloalkyl ring and the other of R³ or R⁴ is selected from H, (C₁-C₆)alkyl, and (C₁-C₆)hydroxyalkyl;

“- - - -” is a bond or is absent;

R⁵ and R⁶ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl, and OH provided that “- - - -” is absent;

R⁷ and R⁸ are each independently selected from H, (C₁-C₆)alkyl, or (C₁-C₆)haloalkyl; or

R⁷ and R⁸ are taken together to form a (C₄-C₁₀)cycloalkyl ring or a (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the foregoing is optionally substituted with one or more substituents;

R¹¹ and R¹² at each occurrence are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy, and (C₁-C₆)hydroxyalkyl;

R¹³ at each occurrence is independently selected from H and (C₁-C₆)alkyl;

Q is absent, —O—, or —NR¹³—;

Z is 1 or 2; and

Y is selected from (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryl wherein any of the foregoing is optionally substituted with one or more substituents; or

Y is NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵ are each independently selected from H, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryl, wherein any of the foregoing, with the exception of H may be optionally substituted with one or more substituents and provided that both R¹⁴ and R¹⁵ are not both H; or

R¹⁴ and R¹⁵ are taken together to form a (C₂-C₉)heterocycloalkyl ring optionally substituted with one or more substituents.

Another aspect of this application is directed to compounds of Formula I having the structure of Formula II:

or salts thereof.

In some embodiments of compounds of Formula II:

A is —(CR⁹R¹⁰)_(n)— and n is 1, 2, or 3 and R⁹ and R¹⁰ at each occurrence are independently selected from H or unsubstituted (C₁-C₆)alkyl, or (C₁-C₆)haloalkyl;

R¹ at each occurrence is independently selected from H, halogen, CN, NO₂, NR¹¹R¹², COR¹³, CO₂R¹³, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)haloalkoxy, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and W is 0, 1, 2 or 3, wherein any of the foregoing, except for H, halogen, CN, and NO₂, is optionally substituted with one or more substituents;

R² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, CO(C₁-C₆)alkyl, CO₂(C₁-C₆)alkyl, CO(C₆-C₁₀)aryl, CO₂(C₆-C₁₀)aryl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, CO(C₃-C₁₀)cycloalkyl, CO₂(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, CO(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, CO₂(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, CO(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, CO₂(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, CO(C₅-C₉)heteroaryl, CO₂(C₅-C₉)heteroaryl, (C₁-C₆)alkyl(C₅-C₉)heteroaryl, CO(C₁-C₆)alkyl(C₅-C₉)heteroaryl, and CO₂(C₁-C₆)alkyl(C₅-C₉)heteroaryl, wherein any of the foregoing, except for H, is optionally substituted with one or more substituents;

R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)aminoalkyl, (C₁-C₆)haloalkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-CON(R¹³)₂, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryloxy, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyloxy, (C₅-C₉)heteroaryl, (C₅-C₉)heteroaryloxy, (C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryloxy, wherein any of the foregoing, except for H, is optionally substituted with one or more substituents; or

R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the foregoing is optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)hydroxyalkyl, COR¹¹, CO₂R¹¹, CONR¹¹R¹³, halogen, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, OR¹³, and oxo; or

R² and one of R³ or R⁴ are taken together to form an optionally substituted (C₃-C₉)heterocycloalkyl ring and the other of R³ or R⁴ is selected from H, (C₁-C₆)alkyl, and (C₁-C₆)hydroxyalkyl;

“- - - -” is a bond or is absent;

R⁵ and R⁶ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl, and OH provided that “- - - -” is absent;

R⁷ and R⁸ are each independently selected from H, (C₁-C₆)alkyl, or (C₁-C₆)haloalkyl; or

R⁷ and R⁸ are taken together to form a (C₄-C₁₀)cycloalkyl ring or a (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the foregoing is optionally substituted with one or more substituents;

R¹¹ and R¹² at each occurrence are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy, and (C₁-C₆)hydroxyalkyl;

R¹³ at each occurrence is independently selected from H and (C₁-C₆)alkyl;

Q is absent, —O—, or —NR¹³—;

Z is 1 or 2; and

Y is selected from (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryl wherein any of the foregoing is optionally substituted with one or more substituents; or

Y is NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵ are taken together to form a (C₂-C₉)heterocycloalkyl ring optionally substituted with one or more substituents.

In another aspect, this application is directed to compounds of Formula I having the structure of Formula IIa:

or salts thereof.

In certain embodiments of compounds of Formula IIa:

-   -   A is —(CR⁹R¹⁰)_(n)— wherein n is 1, 2, or 3 and R⁹ and R¹⁰ at         each occurrence are independently selected from H or         unsubstituted (C₁-C₆)alkyl, or (C₁-C₆)haloalkyl;     -   R¹ at each occurrence is independently selected from H, halogen,         CN, NO₂, NR¹¹R¹², COR¹³, CO₂R¹³, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,         (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)haloalkoxy,         (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl,         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and W is 0, 1, 2 or 3, wherein         any of the foregoing, except for H, halogen, CN, and NO₂, is         optionally substituted with one or more substituents;     -   R² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,         (C₁-C₆)alkyl(C₁-C₆)alkoxy, CO(C₁-C₆)alkyl, CO₂(C₁-C₆)alkyl,         CO(C₆-C₉)aryl, CO₂(C₆-C₉)aryl, (C₆-C₉)aryl,         (C₂-C₆)alkyl(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,         CO(C₃-C₁₀)cycloalkyl, CO₂(C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         CO(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         CO₂(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₂-C₆)alkyl(C₂-C₉)heterocycloalkyl,         CO(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         CO₂(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         (C₂-C₆)alkyl(C₅-C₉)heteroaryl, CO(C₁-C₆)alkyl(C₅-C₉)heteroaryl,         and CO₂(C₁-C₆)alkyl(C₅-C₉)heteroaryl wherein any of the         foregoing, except for H, is optionally substituted with one or         more substituents;

R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, (C₁-C₆)aminoalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-CON(R¹³)₂, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryloxy, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyloxy, (C₅-C₉)heteroaryl, (C₅-C₉)heteroaryloxy, (C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryloxy, wherein any of the foregoing, except for H, is optionally substituted with one or more substituents; or

R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the foregoing is optionally substituted with one or more of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)hydroxyalkyl, COR¹¹, CO₂R¹¹, CONR¹¹R¹³, halogen, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, OR¹³, and oxo; or

R² and one of R³ or R⁴ are taken together to form an optionally substituted (C₃-C₉)heterocycloalkyl ring and the other of R³ or R⁴ is selected from H, (C₁-C₆)alkyl, and (C₁-C₆)hydroxyalkyl;

“- - - -” is a bond or is absent;

R⁵ and R⁶ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl, and OH provided that “- - - -” is absent;

R⁷ and R⁸ are each independently selected from H, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl; or

R⁷ and R⁸ are taken together to form a (C₄-C₁₀)cycloalkyl ring or (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the foregoing is optionally substituted with one or more substituents;

R¹¹ and R¹² at each occurrence are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy, and (C₁-C₆)hydroxyalkyl;

R¹³ at each occurrence is independently selected from H and (C₁-C₆)alkyl;

Z is 1 or 2; and

Y is NR¹⁴R¹⁵ where R¹⁴ and R¹⁵ are each independently selected from H, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, and (C₁-C₆)alkyl(C₅-C₉)heteroaryl, wherein any of the foregoing, with the exception of H may be optionally substituted with one or more substituents and provided that both R¹⁴ and R¹⁵ are not both H.

Another aspect of this application is directed to compounds of Formula I having the structure of Formula III:

or salts thereof.

Another aspect of this application is directed to compounds of Formula I having the structure of Formula III-A

or salts thereof.

In certain embodiments of compounds of Formula III-A:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each selected from H and —OR¹³; Q is absent; Z is 2; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, (C₁-C₆)alkoxy, NO₂, and (C₆-C₁₀)aryl.

Another aspect of this application is directed to compounds of Formula I having the structure of Formula III-B:

or salts thereof.

In certain embodiments of compounds of Formula III-B:

-   -   R² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy,         (C₁-C₆)hydroxyalkyl, (C₁-C₆)alkyl(C₆-C₁₀)aryl,         (C₃-C₁₀)cycloalkyl, CO(C₁-C₆)alkyl and (C₁-C₆)haloalkyl wherein         any of the foregoing, with the exception of H, is optionally         substituted with one or more substituents;     -   R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H;     -   Q is absent; and     -   Y is selected from (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,         (C₂-C₉)heterocycloalkyl, and (C₅-C₉)heteroaryl wherein any of         the foregoing is optionally substituted with one or more         substituents selected from O—(C₁-C₆)alkyl-OR¹³,         O—(C₁-C₆)alkyl-CO₂R¹³, O—(C₁-C₆)alkyl-CN,         O—(C₁-C₆)alkyl-CON(R¹³)₂,         O—(C₁-C₆)alkyl-CO(C₂-C₉)heterocycloalkyl, (C₃-C₁₀)cycloalkyloxy,         (C₁-C₆)alkoxy(C₂-C₉)heterocycloalkyl, CO₂(C₁-C₆)alkyl,         NR¹³CO—(C₁-C₆)alkyl, halogen, OH, CN, NO₂, N(R¹³)₂,         (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,         (C₁-C₆)alkoxy(C₆-C₁₀)aryl, (C₁-C₆)alkoxy, (C₁-C₉)heteroaryl,         (C₄-C₉)heteroaryloxy, (C₁-C₆)alkoxy(C₄-C₉)heteroaryl,         (C₁-C₆)haloalkoxy, OCON(R¹³)₂, (C₂-C₉)heterocycloalkyl,         CON(R¹³)₂, and oxo, wherein any of the foregoing alkyl, alkoxy,         cycloalkyl, heterocycloalkyl, aryl and heteroaryl substituents         is optionally substituted with one or more substituents.

In certain embodiments of compounds of Formula III-B:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is a bond; and Y is selected from (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl, and (C₅-C₉)heteroaryl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments Y is optionally substituted with at least one substituent selected from halogen, OH, CN, NO₂, N(R¹³)₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, (C₂-C₉)heterocycloalkyl, and CON(R¹³)₂.

In other embodiments of compounds of Formula III-B:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; and Y is selected from (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl, and (C₄-C₉)heteroaryl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments Y is optionally substituted with at least one substituent selected from O—(C₁-C₆)alkyl-OR¹³, O—(C₁-C₆)alkyl-CO₂R¹³, O—(C₁-C₆)alkyl-CN, O—(C₁-C₆)alkyl-CON(R¹³)₂, O—(C₁-C₆)alkyl-CO(C₂-C₉)heterocycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₁-C₆)alkoxy(C₂-C₉)heterocycloalkyl, CO₂(C₁-C₆)alkyl, NR¹³CO—(C₁-C₆)alkyl, halogen, OH, CN, NO₂, N(R¹³)₂, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkoxy(C₆-C₁₀)aryl, (C₁-C₉)heteroaryl, (C₄-C₉)heteroaryloxy, (C₁-C₆)alkoxy(C₄-C₉)heteroaryl, (C₁-C₆)haloalkoxy, OCON(R¹³)₂, (C₂-C₉)heterocycloalkyl, CON(R¹³)₂, and oxo, wherein any of the foregoing alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl substituents is optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, CN, halogen, OH, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl and (C₁-C₆)hydroxyalkyl.

In other embodiments of compounds of Formula III-B:

W is 0; R² is selected from (C₁-C₆)alkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, CO(C₁-C₆)alkyl and (C₁-C₆)haloalkyl; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is a bond; Z is 2; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In other embodiments of compounds of Formula III-B:

W is 0; R² is selected from (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, and CO(C₁-C₆)alkyl; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; Z is 2; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In other embodiments of compounds of Formula III-B:

R² is H; “- - - -” is a bond or is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl provided that “- - - -” is absent; R⁹ and R¹⁰ are H; Q is absent; and Y is selected from (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, and (C₃-C₉)heterocycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments Y is optionally substituted with at least one substitutent selected from halogen, N(R¹³)₂, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₃-C₉)heterocycloalkyl, and oxo.

In certain embodiments of compounds of Formula III-B:

W is 0; R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl, (C₁-C₆)aminoalkyl, (C₁-C₆)haloalkyl, (C₃-C₉)heterocycloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-NR¹³—CO(C₁-C₆)alkyl, and (C₁-C₆)alkyl-CON(R¹³)₂; or R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or (C₃-C₉)heterocycloalkyl spirocyclic ring wherein any of the foregoing may be optionally substituted with one or more substituents selected from COR¹³, oxo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and halogen; “- - - -” is a bond; and Y is selected from (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl and (C₃-C₉)heterocycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, N(R¹³)₂, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₃-C₉)heterocycloalkyl, and oxo.

In other embodiments of compounds of Formula III-B:

W is 0; R³ and R⁴ are each independently selected from H and (C₁-C₆)alkyl; or R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or (C₃-C₉)heterocycloalkyl spirocyclic ring; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; R⁷ and R⁸ are H; Z is 2; and Y is (C₆-C₁₀)aryl which is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, N(R¹³)₂, OH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, and (C₁-C₆)haloalkoxy.

In other embodiments of compounds of Formula III-B:

W is 0; R³ and R⁴ are each independently selected from H and (C₃-C₉)heterocycloalkyl, or R³ and R⁴ are taken together to form a (C₃-C₉)heterocycloalkyl spirocyclic ring; “- - - -” is a bond; R⁷ and R⁸ are each independently selected from H and (C₁-C₆)alkyl; and Y is selected from (C₆-C₁₀)aryl and (C₅-C₉)heteroaryl either of which is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, oxo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, N(R¹³)₂, and OH.

In further embodiments of compounds of Formula III-B:

R² is taken together with one of R³ or R⁴ to form an optionally substituted (C₃-C₉)heterocycloalkyl ring and the other of R³ or R⁴ is selected from H and (C₁-C₆)hydroxyalkyl; “- - - -” is a bond; R⁷, R⁸, R⁹, and R¹⁰ are each H; Q is absent; Z is 2; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In additional embodiments of compounds of Formula III-B:

R² is selected from H, C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl; R³ and R⁴ are each H; “- - - -” is either a bond or is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl, provided that “- - - -” is absent; R⁷, R⁸, R⁹, and R¹⁰ are each H; Q is —O—; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₄-C₉)heteroaryl and C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, NR¹³CO—(C₁-C₆)alkyl, (C₄-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)haloalkoxy, (C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryloxy, and NO₂.

In other embodiments of compounds of Formula III-B:

W is 0; R² is H; “- - - -” is absent; and R⁵ and R⁶ are each H.

In other embodiments of compounds of Formula III-B:

W is 0; R² is selected from (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl; “- - - -” is absent; R⁵ and R⁶ are each H; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In additional embodiments of compounds of Formula III-B:

W is 0; “- - - -” is a bond; and Y is (C₄-C₉)heteroaryl optionally substituted with one or more substituents.

In still other embodiments of compounds of Formula III-B:

R² is H; “- - - -” is absent; R⁵ and R⁶ are each H; Q is NR¹³ and R¹³ is (C₁-C₆)alkyl; and Y is (C₄-C₉)heteroaryl optionally substituted with one or more substituents.

Yet another aspect of this application is directed to compounds of Formula I having a structure of Formula III-C:

or salts thereof.

In some embodiments of compounds of Formula III-C:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is a bond; Q is absent; and Y is selected from (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, and (C₃-C₁₀)cycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substitutent selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryloxy, NO₂, CO₂(C₁-C₆)alkyl, CN, NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)haloalkoxy, (C₆-C₁₀)aryl, N(R¹³)₂, and oxo.

In other embodiments of compounds of Formula III-C:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; Q is absent; and Y is selected from (C₆-C₁₀)aryl and (C₅-C₉)heteroaryl wherein either of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, NO₂, (C₆-C₁₀)aryloxy, oxo, NR¹³CO—(C₁-C₆)alkyl, and (C₁-C₆)hydroxyalkyl.

In additional embodiments of compounds of Formula III-C:

W is 0; R² is H; R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₂-C₉)heterocycloalkyl, and (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl; or R³ and R⁴ are taken together to form a (C₃-C₉)heterocycloalkyl spirocyclic ring; R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is a bond; Z is 2; Q is absent; and Y is selected from (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, (C₁-C₆)haloalkyl, and (C₁-C₆)alkoxy.

In still further embodiments of compounds of Formula III-C:

W is 0; R² and one of R³ and R⁴ are taken together to form a (C₃-C₉)heterocycloalkyl ring and the other of R³ and R⁴ is H; “- - - -” is a bond; Z is 2; Q is absent; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents.

In still further embodiments of compounds of Formula III-C:

R² is selected from H, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; Q is —O—; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, and (C₃-C₉)heteroaryl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substitutent selected from halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₃-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryloxy, NR¹³CO—(C₁-C₆)alkyl, (C₆-C₁₀)aryl, and NO₂.

In additional embodiments of compounds of Formula III-C:

W is 0; and R² is H.

In still additional embodiments of compounds of Formula III-C:

W is 0; and R² is selected from (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl.

In still further embodiments of compounds of Formula III-C:

R² is selected from H and CO(C₁-C₆)alkyl; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each H; Q is —NH—; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₃-C₉)heteroaryl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl wherein any of the foregoing may be optionally substituted with one or more substituents.

In yet further embodiments of compounds of Formula III-C: R² is H; and Y is selected from (C₆-C₁₀)aryl, (C₃-C₉)heteroaryl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl wherein any of the foregoing may be optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substitutent selected from (C₁-C₆)alkyl, halogen, and (C₁-C₆)alkoxy.

In still further embodiments of compounds of Formula III-C:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each H; R¹³ is H or methyl; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, or (C₃-C₁₀)cycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and halogen.

In other embodiments of compounds of Formula III-C:

W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each H; Q is absent; Z is 2; and Y is NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵ are taken together to form a (C₂-C₉)heterocycloalkyl ring which is optionally substituted with one or more substituents selected from (C₆-C₁₀)aryl or (C₂-C₉)heterocycloalkyl.

Additional aspects of this application are directed to compounds of Formula I having the structure of Formula III-D:

or salts thereof.

Still additional aspects of this application are directed to compounds of Formula I having the structure of Formula IV:

or salts thereof.

In some embodiments of compounds of Formula IV:

-   -   A is —(CR⁹R¹⁰)_(n)— wherein n is 1, 2, or 3 and R⁹ and R¹⁰ at         each occurrence are independently selected from H or         unsubstituted C₁-C₆ alkyl, or (C₁-C₆)haloalkyl;     -   R¹ at each occurrence is independently selected from H, halogen,         CN, NO₂, NR¹¹R¹², COR¹³, CO₂R¹³, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,         (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)haloalkoxy,         (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl,         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and W is 0, 1, 2 or 3, wherein         any of the foregoing, except for H, halogen, CN, and NO₂, may be         optionally substituted with one or more substituents;     -   R² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,         (C₁-C₆)alkyl(C₁-C₆)alkoxy, CO(C₁-C₆)alkyl, CO₂(C₁-C₆)alkyl,         CO(C₆-C₁₀)aryl, CO₂(C₆-C₁₀)aryl, (C₆-C₁₀)aryl,         (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,         CO(C₃-C₁₀)cycloalkyl, CO₂(C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         CO(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         CO₂(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         CO(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         CO₂(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl,         CO(C₅-C₉)heteroaryl, —CO₂(C₅-C₉)heteroaryl,         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, CO(C₁-C₆)alkyl(C₅-C₉)heteroaryl,         and CO₂(C₁-C₆)alkyl(C₅-C₉)heteroaryl, wherein any of the         foregoing, except for H, is optionally substituted with one or         more substituents;     -   R³ and R⁴ are each independently selected from H, halogen, OH,         (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)aminoalkyl,         (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy,         (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-CON(R¹³)₂,         (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkyl(C₆-C₁₀)aryl,         (C₁-C₆)alkyl(C₆-C₁₀)aryloxy, (C₃-C₁₀)cycloalkyl,         (C₃-C₁₀)cycloalkyloxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyloxy, (C₅-C₉)heteroaryl,         (C₅-C₉)heteroaryloxy, (C₂-C₉)heterocycloalkyl,         (C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyloxy,         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and         (C₁-C₆)alkyl(C₅-C₉)heteroaryloxy, wherein any of the foregoing,         except for H, is optionally substituted with one or more         substituents; or     -   R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or         (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the         foregoing is optionally substituted with one or more of         (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)hydroxyalkyl, COR¹¹,         CO₂R¹¹, CONR¹¹R¹³, halogen, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy,         OR¹³, and oxo;     -   or     -   R² and one of R³ or R⁴ are taken together to form an optionally         substituted (C₃-C₉)heterocycloalkyl ring and the other of R³ or         R⁴ is selected from H or (C₁-C₆)hydroxyalkyl;     -   “- - - -” is a bond or is absent;     -   R⁵ and R⁶ are each independently selected from H, (C₁-C₆)alkyl,         (C₁-C₆)hydroxyalkyl, and OH provided that “- - - -” is absent;     -   R⁷ and R⁸ are each independently selected from H, (C₁-C₆)alkyl,         or (C₁-C₆)haloalkyl; or     -   R⁷ and R⁸ are taken together to form a (C₄-C₁₀)cycloalkyl ring         or (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of         the foregoing is optionally substituted with one or more         substituents;     -   R¹¹ and R¹² at each occurrence are independently selected from         H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy, or         (C₁-C₆)hydroxyalkyl;     -   R¹³ at each occurrence is independently selected from H or         (C₁-C₆)alkyl;     -   Q is absent, or —O—;     -   Z is 1 or 2; and     -   Y is selected from (C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryl,         (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, and         (C₁-C₆)alkyl(C₅-C₉)heteroaryl wherein any of the foregoing is         optionally substituted with one or more substituents; or     -   Y is NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵ are taken together to form a         (C₂-C₉)heterocycloalkyl ring which is optionally substituted         with one or more substituents.

Additional aspects of this application are directed to compounds of Formula I having a structure of Formula IVa:

or salts thereof.

In some embodiments of compounds of Formula IVa:

-   -   A is —(CR⁹R¹⁰)_(n)— wherein n is 1, 2, or 3 and R⁹ and R¹⁰ at         each occurrence are independently selected from H or         unsubstituted C₁-C₆ alkyl, and (C₁-C₆)haloalkyl;     -   R¹ at each occurrence is independently selected from H, halogen,         CN, NO₂, NR¹¹R¹², COR¹³, CO₂R¹³, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,         (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)haloalkoxy,         (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl,         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and W is 0, 1, 2 or 3, wherein         any of the foregoing, except for H, halogen, CN, and NO₂, is         optionally substituted with one or more substituents;     -   R² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,         (C₁-C₆)alkyl(C₁-C₆)alkoxy, CO(C₁-C₆)alkyl, CO₂(C₁-C₆)alkyl,         CO(C₆-C₉)aryl, CO₂(C₆-C₉)aryl, (C₆-C₉)aryl,         (C₂-C₆)alkyl(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,         CO(C₃-C₁₀)cycloalkyl, CO₂(C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         CO(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         CO₂(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₂-C₆)alkyl(C₂-C₉)heterocycloalkyl,         CO(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         CO₂(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         (C₂-C₆)alkyl(C₅-C₉)heteroaryl, CO(C₁-C₆)alkyl(C₅-C₉)heteroaryl,         and CO₂(C₁-C₆)alkyl(C₅-C₉)heteroaryl wherein any of the         foregoing, except for H, is optionally substituted with one or         more substituents;     -   R³ and R⁴ are each independently selected from H, halogen, OH,         (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy,         (C₁-C₆)haloalkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy,         (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-CON(R¹³)₂,         (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₁-C₆)alkyl(C₆-C₁₀)aryl,         (C₁-C₆)alkyl(C₆-C₁₀)aryloxy, (C₃-C₁₀)cycloalkyl,         (C₃-C₁₀)cycloalkyloxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyloxy, (C₅-C₉)heteroaryl,         (C₅-C₉)heteroaryloxy, (C₂-C₉)heterocycloalkyl,         (C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyloxy,         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, and         (C₁-C₆)alkyl(C₅-C₉)heteroaryloxy, wherein any of the foregoing,         except for H, is optionally substituted with one or more; or     -   R³ and R⁴ are taken together to form a (C₄-C₁₀)cycloalkyl or         (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of the         foregoing is optionally substituted with one or more of         (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)hydroxyalkyl, COR¹¹,         CO₂R¹¹, CONR¹¹R¹³, halogen, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy,         OR¹³, and oxo; or     -   R² and one of R³ or R⁴ are taken together to form an optionally         substituted (C₃-C₉)heterocycloalkyl ring and the other of R³ or         R⁴ is selected from H, (C₁-C₆)alkyl, and (C₁-C₆)hydroxyalkyl;     -   “- - - -” is a bond or is absent;     -   R⁵ and R⁶ are each independently selected from H, (C₁-C₆)alkyl,         (C₁-C₆)hydroxyalkyl, and OH provided that “- - - -” is absent;     -   R⁷ and R⁸ are each independently selected from H, (C₁-C₆)alkyl,         or (C₁-C₆)haloalkyl; or     -   R⁷ and R⁸ are taken together to form a (C₄-C₁₀)cycloalkyl ring         or (C₄-C₉)heterocycloalkyl spirocyclic ring wherein either of         the foregoing is optionally substituted with one or more         substituents;     -   R¹¹ and R¹² at each occurrence are each independently selected         from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxy,         and (C₁-C₆)hydroxyalkyl;     -   R¹³ at each occurrence is independently selected from H and         (C₁-C₆)alkyl;     -   Z is 1 or 2; and     -   Y is NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵ are each independently selected         from H, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,         (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,         (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₉)heterocycloalkyl,         (C₁-C₆)alkyl(C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl, and         (C₁-C₆)alkyl(C₅-C₉)heteroaryl, wherein any of the foregoing,         with the exception of H, is optionally substituted with one or         more substituents and provided that both R¹⁴ and R¹⁵ are not         both H.

Additional aspects of this application are directed to compounds of Formula I having a structure of Formula V:

or salts thereof.

Additional aspects of this application are directed to compounds of Formula I having a structure of Formula V-A

or salts thereof.

Further aspects of this application are directed to compounds of Formula I having a structure of Formula V-B:

or salts thereof.

-   -   In some embodiments of compounds of Formula V-B:     -   W is 0;     -   R² is H;     -   R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl,         and (C₁-C₆)haloalkyl; or     -   R³ and R⁴ are taken together to form an optionally substituted         (C₄-C₉)heterocycloalkyl spirocyclic ring;     -   “- - - -” is a bond;     -   R⁷, R⁸, R⁹, and R¹⁰ are each H;     -   Q is absent;     -   Z is 2; and     -   Y is (C₆-C₁₀)aryl optionally substituted with one or more         substituents.

In certain more specific embodiments, Y is optionally substituted with at least one substituent selected from halogen, (C₁-C₆)haloalkyl, and (C₁-C₆)haloalkoxy.

Further aspects of this application are directed to compounds of Formula I having the structure of Formula V-C:

or salts thereof.

Still additional aspects of this application are directed to compounds of Formula I having the structure of Formula V-D:

or salts thereof.

In another aspect, this application relates to salts of the compounds of Formula I wherein the salts are pharmaceutically acceptable salts.

In another aspect, this application relates to compounds of Formula I specifically named herein.

In another aspect, this application relates to compositions comprising one or more compounds of Formula I or a salt thereof. In specific embodiments, the salt is a pharmaceutically acceptable salt. In additional specific embodiments, the composition comprises at least one pharmaceutically acceptable excipient. In other specific embodiments, the composition further comprises at least one additional therapeutically active agent.

In another aspect, this application relates to methods of treating conditions, disorders or diseases mediated, controlled, effected or influenced by a member of the serotonin receptor (5-HT) family. In some embodiments, the condition, disorder or disease is mediated, controlled, effected or influenced by at least one of the 5-HT₆ or 5-HT, receptors. In some specific embodiments, the condition, disorder or disease is: related to the central nervous system (CNS) such as memory disorders, anxiety, epilepsy, migraine, panic attacks, depression, bipolar disorder, obsessive compulsive disorders, cognition/cognitive disorders, mild cognitive impairment (MCl), senile dementia, psychosis, schizophrenia, ADHD/ADD; or for the treatment of pain including neuropathic pain and chronic pain; head trauma or injury; or for the treatment of neurodegenerative conditions, disorders or diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis; or for the treatment of conditions, disorders or diseases related to addiction and/or withdrawal from substances such as narcotics, ethanol (alcoholism), nicotine, and/or benzodiazepines; sleep/wakefulness disorders; or for the treatment of gastrointestinal (GI) conditions, disorders or diseases such as irritable bowel syndrome (IBS), functional bowel disorder; or for the treatment of conditions, disorders or diseases related to feeding behaviors or food intake such as anorexia, cachexia, and obesity.

In another aspect this application relates to methods for improving cognition (cognitive enhancement) and/or improving memory in otherwise healthy subjects.

In another aspect, this application relates to methods of treating conditions, disorders or diseases mediated, controlled, effected or influenced by the 5-HT₆ receptor comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the method further comprises administration of at least one additional therapeutically active agent.

Definitions

The compounds and intermediates described herein may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems.

The various hydrocarbon-containing moieties described herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e. “(C_(a)-C_(b))”. For example, (C_(a)-C_(b))alkyl indicates an alkyl moiety of the integer “a” to the integer “b” carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or group of atoms. For example, the terms “a- to b-membered” or “having between a to b members” or “between a to b substituents” respectively refer to a moiety having the integer “a” to the integer “b” number of atoms or substituents, inclusive.

As used herein by themselves or in conjunction with another term or terms, “alkyl” and “(C₁-C₆)alkyl” refer to straight or branched hydrocarbon groups containing the requisite number of carbon atoms as described above. As used herein, alkyl groups may be optionally substituted with between one to four substituents. Representative examples of alkyl groups include, but are not limited to, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.

As used herein by themselves or in conjunction with another term or terms, “alkoxy” and “(C₁-C₆)alkoxy” refer to straight or branched hydrocarbon groups containing the requisite number of carbon atoms as described above, bonded to an oxygen atom. As used herein, all such alkoxy groups may be optionally substituted with between one to four substituents. Representative examples of alkoxy groups include, but are not limited to, e.g. methoxy, ethoxy, tert-butoxy, etc.

As used herein by themselves or in conjunction with another term or terms, “aminoalkyl” and “(C₁-C₆)aminoalkyl” refer to alkyl groups, as described above, where at least one hydrogen atom, at any position, is replaced by an amino group, i.e., NH₂. As used herein, aminoalkyl groups may be optionally substituted with between one to four substituents.

As used herein by themselves or in conjunction with another term or terms, “alkenyl” and “(C₁-C₆)alkenyl” refer to straight or branched hydrocarbon groups containing the requisite number of carbon atoms as described above, and at least one double bond. As used herein, alkenyl groups may be optionally substituted with between one to four substituents. Representative examples of alkenyl groups include, but are not limited to, e.g. ethenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, etc.

As used herein by themselves or in conjunction with another term or terms, “alkynyl” and “(C₁-C₆)alkynyl” refer to straight or branched hydrocarbon groups containing the requisite number of carbon atoms as described above, and at least one triple bond. As used herein, alkynyl groups may be optionally substituted with between one to four substituents. Representative examples of alkynyl groups include, but are not limited to, e.g. ethynyl, propynyl, butynyl, etc.

As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic conjugated ring systems containing 4 n+2 pi electrons, where n is an integer. As used herein, aromatic refers to and includes ring systems that contain only carbon atoms (i.e. “aryl” or “aromatic carbocycle”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). As used herein, all such aromatic ring systems may be optionally substituted with between one to four substituents.

As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one isolated, i.e. not part of a conjugated pi system, double bond. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S, such as for example, 1,2,5,6-tetrahydropyridine. As used herein, all such non-aromatic ring systems may be optionally substituted with between one to four substituents.

As used herein by themselves or in conjunction with another term or terms, “aryl” and “(C₆-C₁₀)aryl” refer to monocyclic and polycyclic hydrocarbon ring systems, i.e. carbocycles, having the requisite number of carbon atoms as described above, where at least one ring is aromatic, as described above. As used herein, aryl groups may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., phenyl (phenylenyl), napthyl (napthylenenyl), 1,2,3,4-tetrahydro-naphthalenyl, etc.

As used herein by themselves or in conjunction with another term or terms, “arylalkyl” and “(C₁-C₆)alkyl(C₆-C₁₀)aryl” refer to alkyl groups, as defined above, having an aryl group, as defined above, as a substituent. Arylalkyl groups may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., benzyl, phenylethyl, etc.

As used herein by themselves or in conjunction with another term or terms, “aryloxy”, “(C₆-C₁₀)aryloxy”, “alkoxyaryl”, and “(C₁-C₆)alkoxy(C₆-C₁₀)aryl” refer to aryl groups, as defined above, that are bonded directly to an oxygen atom or to an alkoxy group, as defined above, respectively. These groups may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., phenoxy, benzyloxy, phenylethoxy, napthyloxy, etc.

As used herein by themselves or in conjunction with another term or terms, “carbocyclic” and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s),i.e. hydrocarbon ring systems, without regard to aromaticity. Thus, carbocyclic and carbocycle refer to and include ring systems that are saturated or unsaturated, aromatic or non-aromatic, as well as ring systems having fully saturated, aromatic and/or non-aromatic portions. The terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems. Carbocycles may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., cyclopropyl, cyclobutyl, 1,3-dimethylcyclopentyl, cyclohexyl, phenyl, napthyl, cyclohexenyl, 2,3-dihydro-indenyl, 1,2,3,4-tetrahydro-naphthalene, spiro[3.4]octanyl, bicycle[2.2.1]hept-5-enyl, adamantanyl, norbornanyl, bicyclo[2.2.1]heptanyl, etc.

As used herein by themselves or in conjunction with another term or terms, “halo” and “halogen” include fluorine, chlorine, bromine, and iodine atoms and substituents. These groups may also be referred to as fluoro, chloro, bromo and iodo.

As used herein by themselves or in conjunction with another term, “haloalkyl” and “(C₁-C₆) haloalkyl” refer to alkyl groups, as defined above, having one or more hydrogen atoms replaced by halogen atoms, as defined above. It should be understood that where there is more than one halogen atom present in a haloalkyl group, the halogen atoms may be the same or different and/or may be located on the same carbon atom or on different carbon atoms. Representative examples of haloalkyl groups include, but are not limited to, e.g., difluoromethyl, trifluoromethyl, chloromethyl, 3-bromo-2-chloro-propyl, 2,2-dibromoethyl, 2-bromo-2-chloro-ethyl, 1,1,2,2,3,3,4,4-octafluoro-butyl, etc.

As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “(C₁-C₆)haloalkoxy” refer to haloalkyl groups, as defined above, bonded to an oxygen atom. Representative examples of haloalkoxy groups include, but are not limited to, e.g., difluoromethoxy, trifluoromethoxy, chloromethoxy, 2,2-dibromoethoxy, 3-bromo-2-chloro-propoxy, 1,1,2,2,3,3,4,4-octafluoro-butoxy, etc.

As used herein by themselves or in conjunction with another term or terms, “cycloalkyl” and “(C₃-C₁₀)cycloalkyl” refer to monocyclic and polycyclic hydrocarbon ring systems containing the requisite number of carbon atoms as described above, which may be optionally substituted with between one to four substituents. These terms refer to and include ring systems that are fully saturated or contain at least one double or triple bond, as well as ring systems with fully saturated or aromatic or non-aromatic portions, such as, for example, 1,2,3,4-tetrahydro-naphthalenyl. It should be understood that these terms further refer to and include bridged and/or fused polycyclic structures such as, for example, bicyclo[3.2.1]octanyl, bicyclo[5.2.0]nonanyl, bicyclo[2.2.1]hept-5-enyl and the like, as well as spirocyclic ring systems such as, for example, spiro[3.4]octanyl, spiro[3.5]nonyl and the like. Other representative examples of cycloalkyl groups include, but are not limited to, e.g., cyclopropyl, methylcyclopropyl, cyclobutyl, cyclobutenyl, isopropylcyclobutyl, cyclopentyl, 1,3-dimethylcyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 2,3-dihydro-1H-inden-2-yl, norbornyl, decahydronaphthalenyl, etc.

As used herein by themselves or in conjunction with another term or terms, “cycloalkyloxy”, “(C₃-C₁₀)cycloalkyloxy”, “alkoxycycloalkyl”, “alkoxy(C₃-C₁₀)cycloalkyl”, and “(C₁-C₆)alkoxy(C₃-C₁₀)cycloalkyl” refer to a cycloalkyl group having the requisite number of carbon atoms as described above, bonded directly to an oxygen atom or an alkoxy group, respectively. As used herein, these groups may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, 2-cyclopentyl-ethoxy, cyclohexyl-methoxy, cyclohex-3-yloxy, etc.

As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyl”, “(C₂-C₉)heterocycloalkyl”, “heterocycle”, and “heterocyclic” refer to monocyclic and polycyclic ring systems containing the requisite number of carbon atoms as described above and at least one heteroatom selected from N, O, or S. These groups may be optionally substituted with between one to four substituents. These terms further refer to and include ring systems that are fully saturated or contain at least one double or triple bond, as well as ring systems with fully saturated or aromatic portions, such as for example, dihydrobenzo[1,4]-dioxinyl, and/or non-aromatic portions. It should be understood that polycyclic heterocycloalkyl groups further include fused, bridged and spirocyclic ring systems and ring systems in which the N or S is oxidized, i.e. 1,1-dioxide-thiomorpholinyl, 1-oxo-piperidinyl. Additional representative examples of heterocycloalkyl groups include, but are not limited to, e.g., oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, tetrahydrothiopyranyl, thiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, thiomorpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, 1,4-diazepanyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, chromanyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, 7-oxa-1-aza-spiro[4.4]nonanyl, 3-azabicyclo[3.1.0]hexanyl, indolinyl, octahydro-1H-indolyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3,4-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, etc.

As used herein by themselves or in conjunction with another term or terms, “alkylheterocycloalkyl” and “(C₁-C₆)alkyl(C₂-C₉)heterocycloalkyll” refer to alkyl groups, as defined above, having a heterocycloalkyl group, as defined above, as a substituent. Alkylheterocycloalkyl groups may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., piperidinylmethyl, pyrrolidinylethyl, etc.

As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyloxy”, “(C₂-C₉)heterocycloalkyloxy”, “alkoxy(C₂-C₉)heterocycloalkyl” and “(C₁-C₆)alkoxy(C₂-C₉)heterocycloalkyl” respectively refer to a heterocycloalkyl group, as defined above, bonded directly to an oxygen atom or to an alkoxy group, as defined above, and may be optionally substituted with between one to four substituents. Representative examples include, but are not limited to, e.g., pyrrolidin-3-yloxy, piperidin-4-yloxy, azepan-4-yloxy, pyrrolidin-1-yl-ethoxy, pyrrolidin-2-ylmethoxy, tetrahydro-pyran-3-ylpropyloxy, etc.

As used herein by themselves or in conjunction with another term or terms, “heteroaryl”, “(C₅-C₉)heteroaryl”, and “heteroaromatic”, refer to monocyclic and polycyclic aromatic ring systems containing the requisite number of carbon atoms, as described above, and at least one heteroatom selected from N, O, or S. As used herein, a heteroaromatic ring system refers to and includes polycyclic ring systems that contain aromatic portions while other portions of the ring system may be fully saturated or non-aromatic such as, for example, dihydrobenzo[1,4]-dioxinyl. Heteroaromatic rings may be optionally substituted with between one to four substituents. Additional representative examples include, but are not limited to, e.g., pyrrolyl, furanyl, thiophenyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-1H-isoindolyl, 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1,3,4,5-Tetrahydro-benzo[d]azepin-2-one, 2,3,4,5-Tetrahydro-benzo[c]azepin-1-one, 1,2,4,5-Tetrahydro-benzo[c]azepin-3-one, 2,3,4,5-Tetrahydro-1H-benzo[b]azepinyl, 2,3,4,5-Tetrahydro-1H-benzo[d]azepinyl, 2,3,4,5-Tetrahydro-1H-benzo[c]azepinyl, etc.

As used herein, “

” indicates a point of attachment.

As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” indicates that the designated entity such as for example, e.g. carrier, vehicle, diluent, excipient, salt or prodrug, is generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or is generally physiologically compatible with the recipient thereof.

As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, refer to mammals, including humans.

As used herein by itself or in conjunction with another term or terms, “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s) when used in conjunction with the phrase “ . . . optionally substituted by between one to four . . . ” unless otherwise specified.

As used herein, representative examples of substituents include, but are not limited to, e.g., hydrogen (may be denoted as H), halogen (may be denoted as halo), (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₄)alkyl, carboxylic acid (may be denoted as COOH), formyl, (C₁-C₆)acyl, (C₁-C₆) haloalkyl, (C₁-C₆)haloalkoxy, hydroxyl (may be denoted as OH), (C₁-C₆)aminoalkyl, C₆)hydroxyalkyl, nitro (may be denoted as NO₂), cyano (may be denoted as CN), amino (may be denoted as NH₂), mono- or di(C₁-C₆)alkylamino (may be denoted as NHR¹, NR¹R² or N(R¹)₂, oxo (may be denoted as >═O or carbonyl), (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl(C₁-C₆)alkoxy, (C₅-C₉)heteroaryl, (C₅-C₉)heteroaryloxy, (C₁-C₆)alkyl(C₅-C₉)heteroaryl, (C₅-C₉)heteroaryl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl (may be denoted as COOR or CO₂R), (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyloxy, (C₁-C₆)alkyl(C₂-C₉)heterocyclalkyl, (C₂-C₉)heterocycloalkyl(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₁-C₆)alkoxycarbonyl (may be denoted as RCOOR or RCO₂R), (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, mono- and di-(C₁-C₆)alkylaminocarbonyl (may be denoted as NH₂CO, NHCO, NR¹CO, N(R¹)₂CO), (C₁-C₆)acylthio, and (C₁-C₆)acyloxy.

As used herein, “treating”, “treated”, and “treatment”, whether used alone or in conjunction with another term or terms, include preventative (e.g., prophylactic), ameliorative, palliative, and curative uses and results, or any combination thereof. It should be understood that the terms “preventing” and “preventative” and “prophylactic” are not absolute but rather refer to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.

As used herein, the terms “therapeutic” and “therapeutically effective amount”, whether used alone or in conjunction with another term or terms, denote an amount of a compound, composition or medicament that (a) treats or prevents a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder; (c) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)-(c).

As used herein, a “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease or disorder and is not described by Formula I.

The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved (by a regulatory authority such as FDA) for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods.

Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

Certain compounds of Formula I may have two or more asymmetric centers and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, as well as diastereomers and mixtures of different diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.

In practice, resolution and isolation of pure enantiomers can be achieved using methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.

For those compounds of Formula I that contain one or more additional stereogenic centers, those skilled in the art will appreciate that all diastereoisomers and mixtures diastereisomers in any amount of the compounds illustrated and discussed herein are within the scope of the present application. Compounds of Formula I that exist as diastereoisomers may be isolated by methods known to those skilled in the art, for example, by crystallization, gas-liquid or liquid chromatography. Alternatively, intermediates in the course of a synthesis that exist as racemic mixtures may be subjected to resolution by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.

Compounds of the application may be administered as prodrugs. The term “prodrug” refers to a compound that is transformed in vivo to yield a compound of Formula I. The in vivo transformation may occur by various mechanisms, such as hydrolysis, in the blood or other biological fluids.

A prodrug of a compound of Formula I may be formed in a conventional manner with one or more functional groups in the compound, such as an amino, hydroxyl or carboxyl group. For example, if a compound of Formula I contains a carboxylic acid functional group, a prodrug can comprise: (1) an ester formed by the replacement of a hydrogen of the acid group with a group such as (C₁-C₆)alkyl or (C₆-C₁₀) aryl; (2) an activated ester formed by the replacement of the hydrogen of the acid group with groups such as —(CR₂)COOR′, where CR₂ is a spacer and R can be groups such as H or methyl and R′ can be groups such as (C₁-C₆)alkyl or (C₆-C₁₀) aryl; and/or (3) a carbonate formed by the replacement of the hydrogen of the acid with groups such as CHROCOOR′ where R can be groups such as H or methyl and R′ can be groups such as (C₁-C₆)alkyl or (C₆-C₁₀)aryl. Similarly, if a compound of Formula I contains an alcohol functional group, a prodrug can be formed via the replacement of the hydrogen of the alcohol with groups such as (C₁-C₆)alkanoyloxymethyl or (C₁-C₆)alkanoyloxyaryl or by forming an ester via condensation with, for example, an amino acid. Where a compound of Formula I contains a primary or secondary amino group, a prodrug may comprise, for example, an amide formed by the replacement of one or both of the hydrogens of the amino group with (C₁-C₁₀)alkanoyl or (C₆-C₁₀)aroyl. Other prodrugs of amines are well known to those skilled in the art. Alternatively, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.

Discussions regarding prodrugs and their the use can be found in, for example, “Prodrugs as Novel Delivery Systems,” T. Higuchi and W. Stella, Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Further examples of replacement groups may be found in the aforementioned references.

This application also relates to all isotopically-labeled compounds of Formula I. As used herein, the term “isotopically-labeled compound” refers to a compound that has been prepared such that at least one atom has been replaced by an atom having the same atomic number, but a different atomic mass or mass number.

Examples of isotopes that may be incorporated into compounds of Formula I include isotopes of: hydrogen, such as ²H and ³H; carbon, such as ¹¹C, ¹³C, and ¹⁴C; chlorine, such as fluorine, such as ¹⁸F; iodine, such as ¹²³I and ¹²⁵I; nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O; phosphorus, such as ³²P; and sulphur, such as ³⁵S. It should be understood that a compound of Formula (I) may include isotopes of more than one element. For example, a compound of Formula (I) may include isotopes of both hydrogen and carbon.

Certain isotopically-labeled compounds of Formula I such as, for example, those incorporating a radioactive isotope, may be useful in drug and/or substrate tissue distribution or diagnostic studies. In particular, radioactive isotopes such as tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for these purposes in view of their ease of incorporation and ready means of detection.

Other isotopically-labeled compounds of Formula I such as, for example, those incorporating deuterium, i.e. ²H, may have certain therapeutic advantages over unlabeled compounds of Formula (I). Under certain circumstances deuterium labeled compounds can exhibit greater metabolic stability, increased in vivo half-life and/or reduced dosage requirements as compared to the unlabeled version of the compound.

Incorporation of other isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

One of ordinary skill in the art will readily appreciate additional advantages and applications of isotopically-labeled compounds of Formula I as being within the scope of the present disclosure.

Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Preparations and Examples

In general, compounds of Formula I may be prepared by the methods described in the Preparations, Schemes, and Experimental sections of the present application and/or by additional or alternative processes and procedures known in the chemical arts in combination with the knowledge of the skilled practitioner. It should be understood that the methods set forth in the following descriptions, reaction Schemes, Preparations and Experimental sections are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.

Alternative reagents, intermediates, starting materials, synthetic routes and methods can be used or adapted in practice, particularly in light of the scope of the present disclosure in combination with the knowledge of one of ordinary skill in the art. Such alternatives and modifications should be understood as being within the spirit and scope of the present application and the claims.

Unless otherwise indicated, it should be understood that variables appearing in or referred to in the Schemes, and/or Preparations are defined as above or as defined in the Claims. In the reaction schemes below, it should be understood that for compounds where “- - - - - - -” is a bond, R⁵ and R⁶ are absent.

Although specific embodiments and/or individual compounds will be described with reference to particular Schemes, Preparations, and/or Examples, it should be understood that these embodiments and/or compounds are illustrative of a small number (i.e. a subset) of the more general descriptions, genera, subgenera, formulae, species, embodiments and compounds that fall within the scope and spirit of the present application. Accordingly, these specific embodiments and/or compounds should not be interpreted as limiting the scope of the disclosure in any way.

General Synthesis

Schemes I and II depict generalized routes that may be used to prepare the compounds described herein. Methods A through J illustrate more particular aspects of the generalized routes. Preparations A through D describe particular reaction sequences that may be used to make various intermediates. The Examples provide additional detail regarding the synthesis of a number of intermediates and compounds of Formula I.

Method A

As shown in Method A, various compounds of Formula I may be prepared via an Ullmann type coupling reaction. For compounds where PG denotes a protecting group, and G represents a halogen such as iodine, the coupling reaction between the tricyclic halide and a desired thiol, such as Y—SH, may be carried out using a variety of conditions known in the art. Typically, the reaction is conducted using a catalytic amount of CuI (copper iodide), in the presence of neocuproine (2,9-dimethyl-1,10-phenanthroline) or ethylene glycol, and a base, such as sodium tert-butoxide (NaOtBu), in an appropriate solvent, such as N,N-dimethylformamide (DMF) or toluene, at elevated temperatures, such as between about 70-100° C. Other compounds of Formula I may be accessed by coupling the tricyclic halide with an appropriately functionalized trialkylsilyl thioether, such as for example, Y—S-TIPS where TIPS is a triisopropylsilyl group, using CuI in the presence of neocuproine or ethylene glycol and cesium fluoride (CsF) in an appropriate solvent at elevated temperatures. Alternatively, the tricyclic compound can contain the trialkylsilyl thioether, i.e., G is a trialkylsilyl thioether such as S-TIPS, and may be coupled with the desired Y moiety, where Y is functionalized with a suitable leaving group such as a halogen or triflate.

The resulting tricyclic thioether may be oxidized using a reagent such as meta-chloroperoxybenzoic acid (mCPBA) or Oxone® (potassium peroxymonosulfate) in an appropriate solvent, such as methylene chloride (DCM) or tetrahydrofuran (THF). The protecting group (PG) is subsequently removed using procedures well known in the art. For example, where PG is a t-butyl ester (Boc), PG may be cleaved under acidic conditions such as trifluoroacetic acid (TFA) or hydrochloric acid (HCl) in an appropriate solvent, such as DCM or dioxane, or mixture of solvents.

Method B

As shown in Method B, various compounds of Formula I may be prepared via a Pictet-Spengler-type reaction with the appropriately substituted protected or unprotected ketone or aldehyde, followed by the introduction and subsequent oxidation of the thioether. For bicyclic amines where G is a halide such as iodine, condensation and cyclization to the corresponding tricyclic compound is affected via treatment with a strong acid, such as for example TFA, at an appropriate temperature, such as between about 60 to 90° C. In practice, the acid may be used as the solvent for the reaction or may be mixed with an appropriate co-solvent such as, for example, dichloroethane (DCE). For compounds where Q is absent, introduction and subsequent oxidation of the thioether may be accomplished using methods analogous to those described above.

Method C

As shown in Method C, various compounds of Formula I may be prepared by directly coupling a desired sulfone moiety, i.e. where z=2, with a tricyclic halide. Typically, for tricyclic compounds where G represents iodine, the reaction proceeds by stirring together CuI and N,N-dimethyl-1,2-ethanediamine in dimethylsulfoxide (DMSO) for a suitable period of time before the addition of an organic base such as N,N-diisopropylethylamine (DIEA) and the desired sulfinate moiety, such as sodium benzenesulfinate. The reaction is usually conducted at elevated temperatures, such as about 100° C.

Alternatively, to arrive at compounds of Formula I where Q is —NR¹³—, the tricyclic halide, where G is iodine, may be converted to the corresponding alkyl amine. Typically, a tricyclic halide, an alkyl amine, such for example, methylamine, may be stirred together in the presence of a base such as sodium tert butoxide (NaOtBu), neocuproine, and CuI in a suitable solvent such as DMF at elevated temperatures. For compounds where G is hydrogen, nitration followed by reduction provides the corresponding tricyclic amino compound.

Although not shown above, in practice, a protecting group (PG) for the piperidine nitrogen is generally necessary. Treatment of the resulting tricyclic amine or alkyl amine with a desired sulfonyl halide, such as for example, 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride, in the presence of an organic base such as DIEA affords the corresponding sulfonamide. If present, protecting group PG may be removed using standard procedures well known in the art or as described herein.

Method D

As shown in Method D, the moiety Y may be elaborated in a step-wise fashion after installation of the sulfinyl/sulfonyl group. For example, where a tricyclic compound contains a hydroxyl group, denoted above as R—OH, treatment with the appropriate alkyl halide, denoted above as R′-G, affords the corresponding Y moiety. Typically, the O-alkylation reaction proceeds in the presence of a suitable base, such as cesium carbonate (Cs₂CO₃) in an appropriate solvent, such as acetonitrile (ACN). In practice, the reaction may be conducted at elevated temperatures, such as about 60° C.

Alternatively, for tricyclic compounds where G is a halide, introduction of a Y moiety containing a primary or secondary amine, may be affected via a displacement reaction as shown below.

The displacement reaction generally proceeds in the presence of an organic base, such as DIEA, in a suitable solvent, such as DCM or DMF. The protecting group PG may be removed using standard conditions well known in the art or as described herein. Subsequent introduction of the desired R² moiety to the piperidine ring may be affected using the methods described herein as well as other methods known in the art.

Method E

As shown in Method E, various compounds of Formula I may be prepared by N-alkylation of the piperidine ring using conditions well known in the art. For example, treatment with R²—X, where X is a halide, such as bromine, in the presence of a suitable base, such as DIEA, in an appropriate solvent such as DMF affords the corresponding N-alkylated product. Typically, the reaction is conducted at elevated temperatures, such as about 60° C., for a suitable period of time.

Alternatively, for R² moieties in which X is a carbonyl, such as for example, cyclobutanone or benzyaldehyde, or a protected carbonyl, various compounds of Formula I may be prepared via reductive amination. Typically, where Q is a bond or —O—, the reaction proceeds in the presence of acid, such as acetic acid, followed by the addition of a hydride reducing agent such as, for example, sodium triacetoxyborohydride (NaBH(OAc)₃) or sodium cyanoborohydride (NaCNBH₃), to provide the corresponding N-alkylated compound of Formula I. Suitable solvents include THF, DCM, or dichloroethane (DCE).

Method F

As shown in Method F, various compounds of Formula I may be prepared via a Pictet-Spengler-type reaction with the appropriate halo-acetal, such as, for example, 2-(4-bromo-butyl)-[1,3]dioxolane, followed by a second cyclization to form the corresponding tetracyclic compound. Typically, the condensation and subsequent ring closure reaction proceeds in the presence of a strong acid, such as TFA, in a suitable solvent such as dichloroethane (DCE), at elevated temperatures. To affect the second cyclization reaction, the resulting tricyclic halide, where G represents a halide such as, for example, bromine, is treated with a base such as DIEA in an appropriate solvent, such as DMF. In practice this reaction may be conducted at elevated temperatures, such as about 50° C.

Method G

As shown in Method G, various compounds of Formula I can be prepared via hydrogenation using methods well known in the art. For example, for compounds where Q is absent and PG denotes a protecting group such as BOC, treatment with H₂ gas in the presence of palladium on carbon (Pd—C) in an appropriate solvent such as methanol (MeOH) or ethanol (EtOH) provides the corresponding saturated compound. The protecting group PG may then be removed using standard methods well-known in the art or as described herein.

Method H

As shown in Method H, various sulfinyl compounds of Formula I, i.e., where z=1, may be prepared via oxidation with benzenesulfonyl-3-phenyl oxaziridine (Davis reagent). Typically, for compounds where Q is absent and PG denotes a protecting group, the oxidation reaction proceeds in an appropriate solvent, such as for example DCM or tetrahydrofuran (THF) at ambient temperature. Removal of the protecting group is affected using standard procedures well known in the art or as described herein.

Method J

As shown in Method J, various compounds of Formula I where Q is —O— or —NR¹³— may be prepared using the desired halo-sulfonyl/halo-sulfonyl moiety, such as for example 4-chlorobenzenesulfonyl chloride. Typically, for compounds where G is —OH or NH₂, the reaction proceeds in the presence of an organic base such as DIEA in a suitable solvent such as for example, DCM or DCE, or mixtures of solvents. Removal of the protecting group, PG, may be affected using standard procedures well known in the art as well as the methods described herein.

Preparations

Various intermediates useful in the preparation of compounds of Formula I may be synthesized using the general methods provided below.

Preparation A

Various intermediates useful in the preparation of compounds of Formula I may be synthesized according to the sequence shown above or by methods known in the art. As shown in Method A, halophenols and N-protected piperidinols may be coupled in the presence of DEAD (diethyl azodicarboxylate) and triphenyl phosphine (P(Ph)₃) in a suitable solvent such as for example THF or mixture of solvents. In practice the reaction may be conducted at ambient temperature or below.

The resulting haloethers may then be cyclized using tributyltin hydride (Bu₃SnH) and AIBN (2,2′-azobis(isobutyronitrile)) in a suitable solvent, such as toluene. In practice the reaction is conducted at elevated temperatures.

Conversion of the resulting tricyclic adduct to the corresponding alcohol is affected using boron tribromide (BBr₃) in a suitable solvent, such as DCM. In practice the reaction may be conducted at or below ambient temperature.

Additional methods for accessing related intermediates are known in the art. See for example, Tetrahedron Letters, 2001, 42, 6499-6502.

Preparation B

Conversion of the tricyclic phenol to the corresponding halogen, such as for example where Hal represents iodine, can be affected using or modifying standard procedures known in the art. See for example, Synthesis, 2005, 4, 547-550. For example, the tricyclic phenol may be treated with triflic anhydride (Tf₂O) to provide the corresponding trifluoromethanesulfonate, which is subsequently converted to the pinacol boronate ester (not shown) using a palladium catalyst, such as, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), (PdCl₂(dppf)) and pinacol borane, in the presence of a base such as triethyl amine (TEA) and a suitable solvent such as dioxane. Typically, the reaction is conducted at elevated temperatures. Treatment of the resulting tricyclic boronate ester with chloramine-T (N-chloro tosylamide sodium salt) and sodium iodide (NaI) in a mixture of water and THF afforded the corresponding iodotricyclic compound.

Preparation C

Additional intermediates useful in the preparation of compounds of Formula I may be accessed by the route shown above. Various halo-benzofuran-2-ones may be prepared from an appropriately substituted halophenol, where Hal represents a halogen such as bromine or iodine, which when treated with ethyl bromoacetate in the presence of a base, such as potassium carbonate (K₂CO₃) and potassium iodide (KI) in a suitable solvent, such as acetone provides the corresponding halobenzoate. In practice, the reaction may be conducted at elevated temperatures, such as about 50° C. Cyclization of the halobenzoate using LHMDS (lithium bis(trimethylsilyl)amide) in THF at low temperature, and treating the resulting halobenzofuran (not shown) with a strong base, such as sodium hydroxide (NaOH) in a mixture of ethanol and water provides the corresponding halo-benzofuran-2-one. In practice, this reaction is conducted at elevated temperatures, such as about 80° C.

Treatment of the halo-benzofuran-2-one with an appropriate base such as sodium hydride and an appropriately substituted cyanophosphonate, such as for example diethylcyanomethylphosphonate, in a suitable solvent such as THF affords the corresponding halobenzofuran nitrile. After treatment with a strong base such as LHMDS in an appropriate solvent such as THF, the halobenzonitrile can be alkylated using the appropriate alkyl bromide or alkyl iodide. Conversion to the amine may then be affected using an appropriate reducing agent, such as for example diborane, in a suitable solvent, such as THF, at low temperature. Completion of the halotricyclic scaffold may be affected via a Pictet-Spengler cyclization reaction with the appropriate aldehyde or ketone, in the presence of an acid such as acetic acid, hydrochloric acid (HCl) or TFA, optionally in the presence of an organic co-solvent such as toluene or DCM. Compounds represented above as R³R⁴CO are commercially available or may be prepared according to standard methods known in the art.

Still other intermediate compounds may be accessed using or adapting the procedures described in U.S. Pat. No. 5,854,245.

While not expressly included in the reaction scheme, substituted indole compounds, analogous to the substituted benzofurans shown directly above, may be used to prepare tricyclic intermediates using similar methods. Appropriately substituted indole derivatives are commercially available or can be prepared according to or adapted from methods known in the art. See for example, J. Med. Chem., 2005, 48, 1781-1795; Synth. Comm., 1993, 23, 65-72.

Preparation D

Still further useful intermediates may be prepared using the route shown above. Various substituted cyano-benzofuran esters may be prepared from the corresponding phenol using methods and reaction conditions similar to those described in Preparation C. Hydrogenating the cyano-benzofuran ester under about 55 psi of H₂ in the presence of platinum oxide (PtO₂) in acetic acid (AcOH) provides the tricyclic lactam, which is subsequently reduced using lithium aluminium hydride (LAH). Further elaboration of the resulting benzofuropiperidine, i.e. conversion to the corresponding halogenated tricyclic intermediate, may be affecting using the methods described above or procedures known in the art.

Other useful intermediates may be prepared using or adapting the methods described herein or those known in the art. For example, as described in J. Med. Chem. 1989, 32, 2221-2226, various intermediates where R⁵ is not hydrogen may also be prepared from the tricyclic lactam shown above. Specifically, introduction of R⁵ may be affected by treating the tricyclic lactam with an appropriate base, such as sodium hydride (NaH), and the desired alkyl halide, such as for example, chloromethyl cyclopropane, in an appropriate solvent, such as THF. The resulting alkylated product may be reduced to the corresponding benzofuropiperidine using LAH as described above.

Various tricyclic intermediates, especially where A is —(CR⁹R¹⁰)_(n)— and n is 2 or 3 may be prepared using methods known in art such as those described in WO 03/099821.

Other useful intermediates and derivatives not specifically described herein generally may be prepared from appropriately substituted materials using transformations and/or reaction sequences known in the art in combination with the knowledge of one of skill in the art. Such procedures and methods are described in reference books such as, for example, Compendium of Organic Synthetic Methods, Vols. I-VI (Wiley-Interscience) and elsewhere in the chemical literature.

One of skill in the art will appreciate that in some cases protecting groups may be required during a multi-step or single-step reaction sequence. In practice, a protecting group is used to mask or block a particular site/functional group in preparation for a chemical transformation at a different site/functional group in a molecule. After a particular target or transformation is complete or at some specific step later in a synthetic route, the protecting group can be removed using methods well know to those of ordinary skill in the art. The introduction, use and removal of protecting groups is thoroughly described in Protective Groups in Organic Synthesis, (3^(rd) Ed., John Wiley & Sons, 1999).

Compositions

The compounds of Formula I and the pharmaceutically acceptable salts of such compounds may be administered as crystalline or amorphous materials, and may be administered alone or in combination with one or more of the other compounds described herein. In addition, compounds of Formula I and the pharmaceutically acceptable salts of such compounds may be administered in combination with one or more other therapeutically active agents. Generally, the compound(s) will be administered as a formulation, i.e. pharmaceutical composition, in association with one or more pharmaceutically acceptable excipients. The term “excipient” as used herein refers to any ingredient in the formulation other than the compound(s) of Formula I and any additional therapeutically active agent(s) as described above that may be present. Accordingly, excipient refers to and includes ingredients such as, for example: carriers, vehicles, solvents, adjuvants, lubricants, surfactants, binders, buffers, diluents, flavorings, coloring agents/dyes, disintegrants, emulsifying agents, suspending agents, plasticizers, solubilizers, fillers, bulking agents, and the like. The choice of excipient(s) will largely depend on factors such as: the particular mode of administration, the effect of the excipient(s) on solubility, stability, and release profile, and the nature of the dosage form. One skilled in the art will readily appreciate that this list of factors is not exhaustive. The compound(s) of the general Formula I and any additional therapeutically active agents (if present) may be generally referred to as the active ingredient(s) in a formulation or pharmaceutical composition.

Pharmaceutical compositions suitable for the delivery of compounds of Formula I and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule (hard or soft filled), pill, powder, sustained or immediate release formulations, solution, suspension; for parenteral injection as a sterile solution, suspension or emulsion; or for topical administration as an ointment or cream. Additional dosage forms not specifically mentioned herein would be readily appreciated by one of ordinary skill in the art as being within the scope of the present application.

The relative amounts of the active ingredient(s) and the excipient(s) in a formulation or pharmaceutical composition will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) of active ingredient.

A pharmaceutical composition comprising one or more compounds of Formula I may be prepared, packaged, distributed, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of a pharmaceutical composition comprising a predetermined amount of the active ingredient(s). The amount of the active ingredient(s) is generally equal to the dosage of the active ingredient(s) which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

Dosing

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate pharmaceutical compositions in a unit dosage form for ease of administration and uniformity of treatment/therapeutic effect. As used herein, “unit dosage form” or “unit dose”, by themselves or in combination with another term or terms, refer to the physically discreet amount(s) of medication, i.e. the active ingredient(s) in a pharmaceutical formulation, suitable for a one-time administration to the patient or subject to be treated; each unit dose containing a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The more specific composition of the unit dosage forms comprising compounds of Formula I is dictated by and directly dependent on a number of variables, such as, for example: (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount for providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.

It is to be noted that dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present application encompasses intra-patient dose-escalation as determined by the skilled artisan. Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan. As such, one of ordinary skill would readily appreciate and recognize that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

Utility

This application relates to new compounds with affinity for the 5-HT₆ receptor, i.e., 5-HT₆ ligands, which may be useful as active ingredients in pharmaceutical preparations for the treatment of certain conditions, disorders or diseases related to the central nervous system (CNS) such as memory disorders, anxiety, epilepsy, migraine, panic attacks, depression, bipolar disorder, obsessive compulsive disorders, cognition/cognitive disorders, mild cognitive impairment (MCl), senile dementia, psychosis, schizophrenia, ADHD/ADD; or for the treatment of pain including neuropathic pain and chronic pain; head trauma or injury; or for the treatment of neurodegenerative conditions, disorders or diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis; or for the treatment of conditions, disorders or diseases related to addiction or withdrawal from substances such as narcotics, ethanol, nicotine, and/or benzodiazepines; sleep/wakefulness disorders; or for the treatment of gastrointestinal (GI) conditions, disorders or diseases such as irritable bowel syndrome (IBS), functional bowel disorder; or for the treatment of conditions, disorders or diseases related to feeding behaviors or food intake such as anorexia, cachexia, and obesity.

These compounds may also be useful for the improvement of cognition (cognitive enhancement) and/or improvement of memory in otherwise healthy subjects.

Due to its unique localization in the central nervous system the 5-HT₆ receptor is an attractive target for the development of potential treatments for a variety of CNS-related conditions, disorders or diseases. A thorough overview of the distribution and characteristics of the 5-HT₆ receptor can be found in Current Drug Targets—CNS & Neurological Disorders, 2004, 3, 59-79.

There is a growing body of evidence that suggests that compounds with 5-HT₆ receptor affinity, in particular 5-HT₆ receptor antagonists, have potential therapeutic applications in the treatment of cognitive diseases, mild cognitive impairment (MCl), neurodegenerative diseases, schizophrenia, anxiety, and depression. See, for example, Curr Top Med Chem, 2008, 8, 1035-48 (5-HT₆ receptor antagonists and Alzheimer's disease); Curr Opin Drug Discov Devel, 2008, 11, 642-54 (5-HT₆ receptor antagonists and cognitive disorders); Neuropsychobiology 2001, 43, 113-116 (serotonin-6 receptor polymorphism and schizophrenia); Am. J. Med. Genet., 2000, 96, 217-221 (5-HT₆ receptor gene in bipolar affective disorder); Neuropharmacology, 2007, 52, 1274-83 (5-HT₆ antagonist SB-399885 and animal models of anxiety and depression). Pharmacology, Biochemistry, and Behavior, 2005, 81, 673-82 (5-HT₆ receptor antagonists SB-357134 and SB-399885 and improvement in memory formation); Pharmacol. Ther. 2005, 108, 320-333 (5-HT₆ receptors and cognitive enhancement); Neurotherapeutics, 2008, 5, 458-469 (5-HT₆ receptor antagonists as cognitive enhancing agents for Alzheimer's disease); Expert Opin. Invest. Drugs, 2002, 11, 457-467 (serotonin antagonists and depressive disorders).

Serotonin is also known to influence sleep, wakefulness and circadian rhythms, however the specific 5-HT receptor subtypes involved and their respective roles is still under investigation. 5-HT₆ receptors are associated with the hypothalamus, thalamus, and striatum in the brain. These regions are known to be important in the regulation of sleep and wakefulness and recent data in rats appears to confirm that 5-HT₆ receptors may be involved in sleep-wake regulation. Sleep, 2008, 31, 34-44. In this study, rats treated with RO 4368554, a 5-HT₆ receptor antagonist, experienced an increase in non-REM (non-rapid eye movement or NREM) sleep compared to an untreated control group. This observation indicates a possible connection between the 5-HT₆ receptor and sleep quality and/or sleep consolidation (i.e., the ability to maintain sleep continuously with minimal interruption), which in turn suggests a potential use of 5-HT₆ receptor antagonists in the treatment of sleep maintenance insomnia, i.e., the inability to maintain sleep throughout the night.

Association of the 5-HT₆ receptor and/or its mRNA in other areas of the brain, such as the cortex, amygdala, thalamus, periaqueductal grey, spinal cord and dorsal root ganglia implies a potential involvement of the 5-HT₆ receptor in pain and the modulation of nociceptive behaviour. The functional role of the 5-HT₆ receptor in nociception has been recently demonstrated in rats. See European J. Pharmacol., 2007, 569, 59-63. In this study, SB-271046, a 5-HT₆ antagonist, appeared to have a short-lived, antinociceptive effect in a rat model of tonic, persistent pain. The data suggests that 5-HT₆ receptors can modulate the neural substrates involved in nociceptive processing.

The 5-HT₆ receptor has also generated a great deal of interest in connection with the treatment of food-intake or feeding related conditions or disorders. For example, chronic administration of 5-HT₆ receptor antisense oligionucleotides was found to significantly reduce food intake and body mass in rats. J. Psychopharmacol. 1997, 11, A64. Other in vivo studies also indicate that 5-HT₆ antagonists influence feeding behaviour and body weight. See, e.g., Br. J. Pharmacol., 1999, 126, 1537-1542; Int. J. Obes., 2003, 27, Suppl. 1. Abst T1, 1-094; 34^(th) Annu. Meet. Soc. Neurosci. Abstract 75.8. The results of these rat studies suggest that 5-HT₆ antagonists may reduce food intake by enhancing satiety. See Drug Disc Today, 2006, 11, 283-299; Pharmacology & Therapeutics 2008, 117, 207-231.

A small clinical trial in man also appears to suggest that 5-HT₆ may have some influence in food intake or appetite. See, “Treatment of cancer-related anorexia with olanzapine and megestrol acetate: a randomized trial” in Support Care Cancer, published online, Sep. 11, 2009. In this study, olanzapine (OLN), a potent antagonist of the 5-HT₆ receptor, was administered in combination w/megestrol acetate (MA) to patients with cancer-related anorexia (CRA). A second group of patients received only MA. Megestrol acetate is known to be at least partially effective as an appetitie stimulant in cancer patients. However, the group of patients treated with the combination showed significant improvements in appetite, nausea, body weight, and quality of life (improvements in general activity, mood, work, walking, and enjoyment). Whether the 5-HT₆ receptor was a factor in the improvements reported in patients receiving the combination of OLN and MA is unclear, however, the authors hypothesize that the improvement in appetite in the combination treatment group could have been due to the improvement in mood. Other studies have shown that OLN as a single agent improves or reduces nausea in patients with advanced pain and cancer. See J. Pain Symptom Manage., 2002, 23, 526-532; J. Palliative Care, 2003, 6, 251-255; J. Pain Symptom Manage., 2003, 25, 587-582.

Another therapeutic use for 5-HT₆ antagonists may be for the treatment of addiction, such as for example substance and/or alcohol addiction (alcoholism), and in treating withdrawal from drug abuse in particular narcotics, alcohol (alcoholism), nicotine, and benzodiazepines. Novelty-seeking behavior in humans has long been associated with alcoholism and sustance abuse. Psychiatry Res, 1979, 1, 255-264. Traditionally, novelty-seeking behavior has been linked to dopamine-mediated neurotransmission. However, there is evidence that behavioral responses to novelty may also be mediated by 5-HT. A reliable animal model of human novelty-seeking behavior that is highly predictive of drug use has been developed. This model and has recently been used to gain insight into the potential contribution of 5-HT₆ and 5-HT, receptors to novelty-seeking behavior and associated behaviors such as substance abuse. See Neuropsychobiology 1996, 34, 136-145; Exp. Clin. Psychopharmacol 2005, 13, 367-375.

The compounds described herein were tested for their ability to bind to the 5-HT₆ receptor. The ability of the compounds of the formula I to bind to the 5-HT₆ receptor may be measured using the assay and general procedures described below or by methods known in the art. The compounds of Formula I were generally found to be 5-HT₆ ligands, more specifically, the compounds of Formula I were generally found to be 5-HT₆ receptor antagonists.

In some embodiments, compounds of Formula I have an inhibition constant K_(i) of the 5-HT₆ receptor of less than (<) 500 nM.

In other embodiments, compounds of Formula I have an inhibition constant K_(i) to the 5-HT₆ receptor greater than (>) 500 nM but less than (<) 1000 nM.

In still other embodiments, compounds of Formula I have an inhibition constant K_(i) to the 5-HT₆ receptor greater than (>) 1000 nM.

Human 5-HT₆ Receptor Binding Assay

Membrane Preparation

Membranes were prepared from CHO—K1 cells stably transfected with the human 5-HT₆ receptor (Euroscreen; ES-316-C). The cells were grown in Gibco Advanced DMEM-F12 (Cat#12634010) containing 2% dialyzed FBS (Hyclone Cat#SH30079.03). The cells were harvested in phosphate buffered saline (PBS) containing 0.1 mM EDTA and pelleted by centrifugation (1000×g), the supernatant was discarded and the pellets were stored at −80° C. prior to membrane preparation. Membranes were prepared as previously described (J Bio Chem. 1992, 267 (14) 9844-51). Briefly, frozen cell pellet was resuspended in a lysis buffer containing 5 mM Tris-HCl (pH 7.5), 5 mM EDTA and 1 complete EDTA-free protease inhibitor tablet (Roche Applied Science, Indianapolis, Ind.) per 50 mL buffer, and homogenized with a tissue homogenizer. The cell lysate was then centrifuged at 40,000×g for 30 min at 4° C. to collect the membranes. The membrane pellets were washed in membrane buffer (50 mM Tris-HCl (pH 7.5), 0.6 mM EDTA, 5 mM MgCl₂, 1 complete EDTA-free protease inhibitor tablet per 50 mL buffer) using a tissue homogenizer. The membranes were centrifuged at 40,000×g for 30 min at 4° C. and the pellets were resuspended in membrane buffer containing 250 mM sucrose, and protein concentration was determined using the Coomassie Plus kit (Pierce Biotechnology, Rockford, Ill.).

Receptor Binding Assays

Membranes prepared from cells expressing recombinant human 5-HT₆ receptor (h5-HT₆) were resuspended in assay buffer containing 50 mM Tris HCl, (pH7.4), 4 mM CaCl₂, 10 μg/mL saponin, and 0.1% (w/v) ascorbic acid. Membranes were preincubated using 1.75 μg membrane protein and 0.25 mg FlashBlue scintillation beads (PerkinElmer catalogue #FB001) per well at 4° for 30 min. Vehicle or test compound, and 4 nM [³H]LSD (Perkin Elmer catalogue #NET638) were added and incubated for 3 hours at room temperature in a final volume of 80 μL in a 96-well plate. Test compounds or assay controls for total and non-specific binding were diluted in DMSO as 100× solutions and serially diluted by half log concentrations on a Perkin Elmer JANUS Automated Workstation. Serotonin (10 μM final concentration) was used to determine non-specific binding in the assay. Plates were read using the Microbeta Trilux 1450 LSC and luminescence counter. Data were analyzed by nonlinear repression using the dose-response equation (variable slope) to calculate IC₅₀ in XLfit4 (ID Business Solutions Inc.): y=(Bottom+((Top−Bottom)/(1+((IC₅₀ /x)^Hill slope))))

Binding of [³H]LSD to the h5-HT₆ membranes was saturable with B_(max)=6.2 μmol/mg protein and K_(d)=2.3 nM. K_(i) value was then calculated according to the Cheng-Prusoff method using the equation below (Cheng and Prusoff, 1973): K _(i,app)=IC₅₀/(1+[radioligand]/K _(d)))

Compounds of Formula I were tested according to procedures described above. The results are set forth below in Table 1 according to the following key:

A=K_(i)<500 nM

B=K_(i)>500 nM and <1000 nM

C=K_(i)>1000 nM

h5-HT6 Ex No. (Ki, nM) 1 A 2 A 3 A 4 A 5 B 6 C 7 C 8 C 9 C 10 A 11 A 12 A 13 C 14 C 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 A 23 A 24 A 25 A 26 A 27 A 28 A 29 A 30 A 31 A 32 A 33 A 34 A 35 36 A 37 A 38 A 39 A 40 A 41 A 42 B 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 C 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 C 71 C 72 C 73 A 74 A 75 C 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 C 92 C 93 B 94 A 95 A 96 C 97 C 98 A 99 A 100 A 101 A 102 A 103 A 104 C 105 A 106 A 107 A 108 A 109 A 110 A 111 A 112 A 113 A 114 A 115 C 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 C 125 A 126 A 127 A 128 A 129 B 130 A 131 A 132 C 133 A 134 A 135 C 136 A 137 A 138 C 139 C 140 A 141 A 142 C 143 A 144 C 145 C 146 A 147 A 148 A 149 A 150 A 151 B 152 A 153 A 154 C 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 A 163 A 164 A 165 A 166 A 167 A 168 B 169 B 170 A 171 C 172 A 173 C 174 C 175 A 176 A 177 C 178 A 179 A 180 C 181 C 182 A 183 A 184 A 185 A 186 A 187 B 188 A 189 A 190 C 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A 200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 214 A 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 A 225 A 226 C 227 A 228 B 229 A 230 A 231 A 232 A 233 C 234 C 235 A 236 A 237 A 238 A 239 A 240 A 241 A 242 C 243 A 244 A 245 A 246 A 247 A 248 A 249 A 250 A 251 A 252 A 253 C 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 A 264 A 265 A 266 A 267 A 268 A 269 B 270 A 271 C 272 B 273 A 274 A 275 B 276 A 277 A 278 A 279 A 280 C 281 C 282 A 283 A 284 A 285 C 286 A 287 A 288 A 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 A 298 A 299 A 300 A 301 A 302 A 303 A 304 A 305 A 306 A 307 A 308 309 310 311 A 312 A 313 A 314 A 315 A 316 A 317 A 318 A 319 A 320 A 321 A 322 A 323 C 324 A 325 B 326 A 327 C 328 A 329 C 330 C 331 B 332 A 333 A 334 B 335 C 336 C 337 C 338 A 339 A 340 A 341 A 342 A 343 A 344 B 345 A 346 A 347 A 348 A 349 A 350 A 351 C 352 C 353 A 354 A 355 C 356 B 357 A 358 A 359 A 360 A 361 A 362 A 363 A 364 A 365 A 366 A 367 A 368 A 369 C 370 A 371 A 372 A 373 C 374 C 375 A 376 A 377 C 378 A 379 A 380 C 381 A 382 A 383 C 384 A 385 C 386 A 387 C 388 A 389 C 390 A 391 C 392 A 393 C 394 A 395 A 396 C 397 C 398 A 399 A 400 A 401 A 402 A 403 A 404 A 405 B 406 A 407 A 408 A 409 A 410 B 411 A 412 A 413 A 414 A 415 A 416 A 417 A 418 A 419 A 420 A 421 A 422 A 423 A 424 A 425 C 426 A 427 A 428 C 429 C 430 A 431 C 432 A 433 A 434 A 435 C 436 A 437 A 438 A 439 A 440 A 441 A 442 C 443 C 444 C 445 C 446 A 447 C 448 A 449 A 450 C 451 A 452 A 453 C 454 A 455 C 456 A 457 A 458 C 459 C 460 A 461 A 462 C 463 A 464 A 465 A 466 A 467 A 468 A 469 A 470 A 471 A 472 A 473 A 474 C 475 476 C 477 C 478 B 479 C 480 A 481 A 482 A 483 A 484 A 485 A 486 A 487 A 488 A 489 A 490 A 491 A 492 A 493 A 494 A 495 A 496 A 497 A 498 A 499 A 500 A 501 A 502 A 503 A 504 A 505 A 506 A 507 A 508 A 509 A 510 A 511 C 512 A 513 A 514 A 515 C 516 A 517 A 518 C 519 B 520 A 521 A 522 A 523 A 524 A 525 A 526 527 528 529 530 A 531 A 532 B 533 A 534 A 535 A 536 A 537 A 538 A 539 A 540 A 541 A 542 A 543 A 544 B 545 A 546 A 547 A 548 A 549 A 550 B 551 A 552 553 A 554 A 555 A 556 A 557 A 558 B 559 A 560 C 561 A 562 A 563 C 564 C 565 A 566 A 567 A 568 A 569 A 570 A 571 A 572 A 573 A 574 A 575 A 576 A 577 A 578 A 579 A 580 A 581 A 582 A 583 A 584 A 585 A 586 A 587 A 588 A 589 A 590 A 591 A 592 A 593 A 594 A 595 A 596 A 597 B 598 A 599 A 600 A 601 A 602 A 603 A 604 A 605 B 606 A 607 A 608 A 609 A 610 B 611 A 612 A 613 C 614 A 615 A 616 A 617 A 618 C 619 A 620 A 621 A 622 A 623 C 624 A 625 A 626 C 627 A 628 A 629 A 630 A 631 A 632 A 633 A 634 A 635 A 636 A 637 C 638 A 639 C 640 C 641 A 642 A 643 A 644 A 645 C 646 B 647 A 648 A 649 A 650 A 651 A 652 B 653 A 654 A 655 A 656 A 657 A 658 A 659 C 660 A 661 A 662 A 663 A 664 A 665 A 666 A 667 C 668 A 669 A 670 A 671 A 672 A 673 A 674 A 675 A 676 A 677 A 678 A 679 A 680 A 681 A 682 A 683 B 684 B 685 C 686 A 687 A 688 B 689 C 690 C 691 C 692 A 693 A 694 A 695 C 696 C 697 C 698 A 699 A 700 A 701 C 702 C 703 C 704 A 705 A 706 A 707 B 708 B 709 B 710 A 711 A 712 C 713 A 714 A 715 A 716 A 717 A 718 A 719 A 720 A 721 A 722 B 723 B 724 A 725 A 726 A 727 B 728 C 729 A 730 C 731 A 732 B 733 B 734 C 735 C 736 C 737 A 738 A 739 A 740 A 741 A 742 A 743 A 744 C 745 C 746 C 747 B 748 A 749 C 750 C 751 C 752 C 753 C 754 C 755 C 756 C 757 C 758 A 759 C 760 C 761 C 762 C 763 C 764 B 765 B 766 B 767 C 768 B 769 A 770 C 771 A 772 A 773 A 774 C 775 A 776 C 777 C 778 C 779 C 780 C 781 C 782 C 783 B 784 A 785 C 786 A 787 C 788 A 789 C 790 C 791 A 792 A 793 A 794 A 795 A 796 A 797 A 798 C 799 B 800 C 801 C 802 B 803 C 804 C 805 C 806 C 807 C 808 C 809 C 810 C 811 C 812 C 813 C 814 C 815 C 816 B 817 C 818 A 819 A 820 A 821 C 822 C 823 A 824 C 825 A 826 A 827 A 828 A 829 A 830 A 831 C 832 C 833 B 834 A 835 A 836 C 837 C 838 B 839 C 840 C 841 C 842 C 843 C 844 C 845 C 846 C 847 C 848 C 849 C 850 C 851 C 852 C 853 B 854 C 855 C 856 A 857 C 858 C 859 C 860 C 861 B 862 C

Specific data for a select number of compounds is provided below:

h5-HT₆ Ex. No. Chemical name (K_(i), nM) 1 7-[(3-fluorophenyl)sulfonyl]-1,1- 1.5 dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3-c]pyridine 99 6-[(2-fluorophenyl)sulfonyl]-4a-methyl- 243.1 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3-c]pyridine 161 7-{[3-(trifluoromethyl)phenyl]sulfonyl}- 44.0 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3-c]pyridine 343 7-[(6-methylpyridin-2-yl)sulfonyl]- 6.6 1,2,3,4-tetrahydro[1]benzofuro[2,3- c]pyridine 527 7-[(3-fluorophenyl)sulfonyl]-1- 93.0 (trifluoromethyl)-2,3,4,9-tetrahydro-1H- beta-carboline 608 7-(phenylsulfonyl)-2-(propan-2-yl)- 49.4 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3-c]pyridine 660 1,2,3,4,4a,9a- 11.4 hexahydro[1]benzofuro[2,3-c]pyridin-7-yl naphthalene-2-sulfonate 820 N-(1,2,3,4,4a,9a- 471.5 hexahydro[1]benzofuro[2,3-c]pyridin-6- yl)-2,5-dimethylbenzenesulfonamide

EXAMPLES

The following non-limiting Examples and Preparations illustrate the preparation of compounds of the present application. Proton (¹H) Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (6) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The mass spectra (m/z) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). The following abbreviations have been used for common solvents, reagents or reaction conditions: CDCl₃, deuterochloroform; D₆-DMSO, deuterodimethylsulphoxide; CD₃OD, deuteromethanol; THF, tetrahydrofuran; DCM, dichloromethane; TFA, trifluoroacetic acid, MeCN, AcCN, or ACN, acetonitrile; DMF, N,N-dimethylformamide; DMSO, dimethylsulfoxide; MeOH, methanol; mCPBA, meta-chloroperbenzoic acid; HCl, hydrochloric acid; DIEA, N,N-diethylisopropyl amine; DBU, (1,8-diazabicyclo[5.4.0]undec-7-ene); EtOAc, ethyl acetate; rt, RT or r.t., room temperature; h.v., house vacuum; dec., decomposition; SFC, supercritical fluid chromatographie. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F₂₅₄ plates, R_(f) is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.

Preparative LC-MS

Various compounds described below were purified using preparative LC-MS. Unless otherwise described, the compounds were purified using a WATERS Fractionlynx system equipped with a YMC Pack Pro C₁₈ Column (5 μm, 120 Å, 50×20 mm) and the following solvent system: H₂O, AcCN, and 2% TFA in H₂O, Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general all elution gradients of H₂O and MeCN were run over a 7 minute run time with a flow rate of 35 mL/min. An autoblend method was used to ensure a concentration of 0.1% TFA throughout each run.

Alternatively, the compounds were purified using a WATERS Fractionlynx system equipped with a XBridge Prep O₁₈ OBD Column (5 μm, 30×75 mm) using the solvent system and autoblend method described above. Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general all elution gradients of H₂O and MeCN were run over a 8 minute run time with a flow rate of 50 mL/min.

Analytical LC-MS

Analytical LC-MS was performed on a WATERS Acquity UPLC-MS instrument equipped with a ACQUITY UPLC BEH C₁₈ Column (2.1×50 mm, 1.7 μm), a column temperature of 45° C. and using the following solvent system: Solvent A: 0.1% HCOOH in H₂O; and Solvent B: 0.1% HCOOH in AcCN. All compounds were run using the same elution gradient, i.e., 5% to 95% Solvent B over a 1.5 min run time with a flow rate of 0.6 mL/min.

Preparative Chiral SFC Separation

Stereoisomer mixtures were separated using a Berger Minigram SFC instrument on one of the following columns: ChiralPak AS-H (10×250 mm), ChiralPak IA (10×250 mm), ChiralPak AD-H (21×250 mm), Phenomenex Lux-2 (21.2×250 mm), or ChiralPak IC (10×250 mm); eluting with either 0.1% diethylamine in MeOH/CO₂, or 0.1% diethylamine in EtOH/CO₂ or 0.1% diethylamine in isopropanol/CO₂ with a flow rate of 2.5 mL/min and a column temperature of 35° C.

Analytical Chiral SFC Separation

Stereoisomer mixtures or single enantiomers were analyzed using a JASCO analytical SFC instrument on one of the following columns: ChiralPak AS-H (4.6×250 mm), ChiralPak IA (4.6×250 mm), ChiralPak AD-H (4.6×250 mm), Phenomenex Lux-2 (4.6×250 mm), or ChiralPak IC (4.6×250 mm); eluting with either 0.1% diethylamine in MeOH/CO₂, or 0.1% diethylamine in EtOH/CO₂ or 0.1% diethylamine in isopropanol/CO₂, with a flow rate of 6.0 mL/min and a column temperature of 35° C.

It should be understood that for the dihydrofuranopyridine compounds, i.e., compounds where “- - - - - - -” is absent, the configuration at the ring juncture is cis. For examples where a racemic mixture is subjected to chiral separation, the absolute stereochemistry of the isolated compounds was not determined.

Example 1 7-[(3-Fluorophenyl)sulfonyl]-1,1-dimethyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine

Step 1 7-(3-Fluoro-phenylsulfanyl)-1,1-dimethyl-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

To tert-butyl 7-iodo-1,1-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P30 (0.505 g, 1.18 mmol) was added sodium tert-butoxide (341 mg, 3.55 mmol), copper(I) iodide (20 mg, 0.08 mmol), 1,2-ethanediol (132 μL, 2.38 mmol), N,N-dimethylformamide (17 mL, 210 mmol), and finally 3-Fluoro-benzenethiol (101 μL, 1.19 mmol). The reaction mixture was flushed with N₂ and heated at 120° C. under N₂. After 15 h, the reaction mixture was concentrated under high vacuum, the residue dissolved in 5% methanol-methylene chloride and then filtered through a celite-silica plug. The filtrate was concentrated and purified by silica chromatography (EtOAc/hexane) to afford the product as a pale yellow oil. MS m/z: 428 [M+H]⁺.

Step 2 7-(3-Fluoro-benzenesulfonyl)-1,1-dimethyl-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

To a solution of 7-(3-fluoro-phenylsulfanyl)-1,1-dimethyl-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.440 g, 1.03 mmol) in methylene chloride (25.00 mL, 390.0 mmol) was added m-CPBA 70-75% (533 mg, 2.16 mmol) portionwise with stirring. After completion, the reaction mixture was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, dried (Na₂SO₄) and concentrated. Purification by silica chromatography (EtOAc/hexane) afforded a white solid. mp 58-60° C.; MS m/z: 360 [M-Boc+H]⁺.

Step 3 7-(3-Fluoro-benzenesulfonyl)-1,1-dimethyl-1,2,3,4-tetrahydrobenzo[4,5]furo[2,3-c]pyridine

7-(3-Fluoro-benzenesulfonyl)-1,1-dimethyl-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.200 g, 0.435 mmol) in 4M HCl in dioxane (5.0 mL, 57.7 mmol) was stirred at rt. After 4 h, the heterogenous mixture was concentrated and triturated with Et₂O. The resulting white precipitate was dried under vacuum at 80° C. for 15 h. mp 110-114° C.; MS m/z 360 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.7 (s, 6H), 3.0 (m, 2H), 3.5 (m, 2H), 7.5 (m, 1H), 7.7 (m, 1H), 7.9 (m, 4H), 8.3 (s, 1H), 10.0 (brs, 2H).

The following examples were prepared essentially as described in the above synthetic procedures. The enantiomers Example 20 and Example 21 in the Table below were isolated from the corresponding racemic mixture Example 12 using SFC chromatography on a chiral column as described in the general method. All compounds were isolated as HCl salts unless otherwise stated.

Mp MS m/z Ex. # Name (° C.) [M + H]⁺ Stereochemistry Starting material 1 7-[(3-fluorophenyl)sulfonyl]- 320-325 360 3-fluorobenzenethiol 1,1-dimethyl-1,2,3,4- dec. tetrahydro[1]benzofuro[2,3- c]pyridine 2 7-[(3-fluorophenyl)sulfonyl]- 286-288 430 3-fluorobenzenethiol 4,4-dimethyl-2′,3,3′,4,5′,6′- hexahydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,4′-pyran] 3 7-[(2- 222-224 360 racemic 2-methoxybenzenethiol methoxyphenyl)sulfonyl]- 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 4 7-[(3- 279-280 360 racemic 3-methoxybenzenethiol methoxyphenyl)sulfonyl]- 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 5 7-[(4- 283-284 360 racemic 4-methoxybenzenethiol methoxyphenyl)sulfonyl]- 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 6 4a-methyl-7-[(6- 255-258 345 racemic 6-methylpyridine-2-thiol methylpyridin-2-yl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 7 4a-methyl-7-[(4- 199-201 346 racemic 4-methylpyrimidine-2- methylpyrimidin-2- thiol yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 8 4a-methyl-7-(pyridin-2- 282-283 331 racemic pyridine-2-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 9 4a-methyl-7-(pyrimidin-2- 232-234 332 racemic pyrimidine-2-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 10 7-[(3- 271-273 374 racemic 3-ethoxybenzenethiol ethoxyphenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 11 7-[(3-fluorophenyl)sulfonyl]- 288-290 348 racemic 3-fluorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 12 4a-methyl-7-{[3-(propan-2- 206-208 388 racemic 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 13 4a-methyl-6-(pyridin-4- 186-188 331 racemic pyridine-4-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 14 4a-methyl-6-[(1- 207-210 347 racemic pyridine-4-thiol oxidopyridin-4-yl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 15 1,1-dimethyl-7-{[3-(propan- 243-245 400 3-(propan-2- 2-yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 16 7-[(3- 335 372 3-methoxybenzenethiol methoxyphenyl)sulfonyl]- dec. 1,1-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 17 7-[(3- >200 376 3-chlorobenzenethiol chlorophenyl)sulfonyl]-1,1- dec. dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 18 7-[(3-chloro-4- >200 394 3-chloro-4- fluorophenyl)sulfonyl]-1,1- dec. fluorobenzenethiol dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 19 1,1-dimethyl-7-[(6- 305-310 357 6-methylpyridine-2-thiol methylpyridin-2-yl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 20 4a-methyl-7-{[3-(propan-2- 184-185 388 Enantiomer 1 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 21 4a-methyl-7-{[3-(propan-2- 183-184 388 Enantiomer 2 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 22 7-[(3-Fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]

Step 1 7-[(3-Fluorophenyl)sulfanyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]

7-Iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (0.20 g, 0.56 mmol), neocuproine (11.6 mg, 0.0558 mmol) and copper(I) iodide (53.1 mg, 0.279 mmol) were dissolved into the anhydrous DMF (4 mL, 50 mmol) in a 20 mL scintillation vial under N₂. 3-Fluoro-benzenethiol (104 μL, 1.23 mmol) was added neat followed immediately by the addition of the sodium tert-butoxide (118 mg, 1.23 mmol). The reaction vial was capped with a teflon coated cap and the mixture was stirred at 100° C. overnight. After 15 h, the reaction was cooled to room temperature and concentrated under vacuum. The residual solid was partially dissolved into a 5% MeOH in DCM solution and flushed through a Celite plug. The concentrated filtrate was chromatographed on silica gel using DCM-MeOH—NH₄OH to afford a brownish oil, used directly in the next step.

Step 2 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]

To a solution of 7-[(3-fluorophenyl)sulfanyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (0.160 g, 0.433 mmol) in methanol (5.0 mL, 120 mmol) was added a solution of Oxone® (0.666 g, 1.08 mmol) in water (5.0 mL, 280 mmol) and the mixture was stirred at rt overnight. After 3 h, the reaction mixture was filtered, concentrated, and then extracted with DCM/sat. aq. NaHCO₃. The extract was dried, concentrated and then purified by silica gel chromatography (DCM-MeOH—NH₄OH) to afford an off-white solid. The product was converted to the HCl salt using excess EtOH—HCl and dried overnight at 80° C. under high vacuum. mp 285-290° C. dec.; MS m/z 401 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): d 1.7 (d, J=12.6 Hz, 1H), 1.83 (d, J=14.2 Hz, 1H), 2.0 (m, 2H), 2.3 (m, 1H), 2.7 (m, 2H), 3.2 (m, 2H), 3.6 (m, 1H), 3.7 (d, J=11.5 Hz, 1H), 3.85 (d, J=12 Hz, 1H), 4.0 (d, J=10.6 Hz, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 8.08 (s, 1H).

The following examples were prepared essentially as described above. Example 50 and Example 51, in the Table below were isolated from racemic mixture Example 40, and similarly, Example 52 and Example 53 were isolated from the corresponding racemic mixture Example 30 using SFC chromatography on a chiral column as described in the general method. All compounds were isolated as HCl salts unless otherwise stated.

Ex. MS m/z # Name Mp (° C.) [M + H]⁺ Stereochemistry Salt Starting material 23 7-{[3-(propan-2- 148-155 442 Racemic HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- dec. yloxy)benzenethiol 3,4,5′,6′-tetrahydro-2H,4′H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-pyran] 24 7-[(3,5- 85-95 420 Racemic 3,5- difluorophenyl)sulfonyl]- difluorobenzenethiol 3,4,5′,6′-tetrahydro-2H,4′H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-pyran] 25 7-[(3- >200 dec. 372 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-3,4- dihydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,1′-cyclobutane] 26 7-{[3-(propan-2- >200 dec. 412 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}-3,4- yloxy)benzenethiol dihydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,1′-cyclobutane] 27 1-ethyl-7-[(3- >300 374 A mixture of HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- diastereomers methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 28 7-[(3- >250 386 0 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-3,4- dihydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,1′-cyclopentane] 29 1-cyclopropyl-7-[(3- >250 dec. 386 Racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 30 7-[(3- 89-93 388 Racemic 3-fluorobenzenethiol fluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 31 7-{[3-(propan-2- 261-263 428 enantiomer 1 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- dec. yloxy)benzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 32 7-{[3-(propan-2- 259-261  428) enantiomer 2 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- dec. yloxy)benzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 33 1-(ethoxymethyl)-7-[(3- 230-250 390 Racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]- dec. 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 34 1-(difluoromethyl)-1- 219-222 436 single enantiomer HCl 3-(propan-2- methyl-7-{[3-(propan-2- of unknown yloxy)benzenethiol yloxy)phenyl]sulfonyl}- configuration 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 35 1,1-bis(fluoromethyl)-7-[(3- 154-157 396 3-fluorobenzenethiol fluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 36 7-[(3- 284-286 402 Racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- methyl-1-(2-methylpropyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 37 7-[(3- 225-228 414 Racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- methyl-1-(trifluoromethyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 38 7-[(3- 298-300 450 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]- dec. 2′,3,3′,4,5′,6′-hexahydro- 2H-spiro[1-benzofuro[2,3- c]pyridine-1,4′-thiopyran] 1′,1′-dioxide 39 7-[(3- 196-198 420 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1,1- bis(methoxymethyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 40 2-{7-[(3- 220-223 431 Racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridin-1-yl}-N,N- dimethylacetamide 41 1-{7-[(3-   256 dec. 443 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-3,4- dihydro-1′H,2H-spiro[1- benzofuro[2,3-c]pyridine- 1,4′-piperidin]-1′- yl}ethanone 42 6-[(3- >200 360 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1,1- dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 43 7-[(3- >200 402 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]- 2′,3,3′,4,5′,6′-hexahydro- 2H-spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 44 7-{[3-(propan-2-   250 dec. 442 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 2′,3,3′,4,5′,6′-hexahydro- 2H-spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 45 7-[(3- 248-252 444 racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-4,4- dimethyl-1-(tetrahydro-2H- pyran-4-yl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 46 7-[(3- 263-268 416 racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-4,4- dimethyl-3,4,4′,5′- tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,3′-furan] 47 7-[(3-fluorophenyl)sulfinyl]- 248-253 414 racemic HCl 3-fluorobenzenethiol 4,4-dimethyl-2′,3,3′,4,5′,6′- hexahydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,4′-pyran] 48 7-[(3- 153-155 374 3-fluorobenzenethiol fluorophenyl)sulfonyl]-3,4- dihydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,3′-oxetane] 49 7-[(3- >200 390 racemic HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- (methoxymethyl)-1-methyl- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 50 2-{7-[(3- 230-233 431 Enantiomer 1 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridin-1-yl}-N,N- dimethylacetamide 51 2-{7-[(3- 230-233 431 Enantiomer 2 HCl 3-fluorobenzenethiol fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridin-1-yl}-N,N- dimethylacetamide 52 7-[(3- 318-320 388 enantiomer 1 HCl Mixture of 7-[(3- fluorophenyl)sulfonyl]- dec. fluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] c]pyridine-1,3′-furan] 53 7-[(3- 315-317 388 enantiomer 2 HCl Mixture of 7-[(3- fluorophenyl)sulfonyl]- dec. fluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] c]pyridine-1,3′-furan]

Examples 54 and 55 Racemic Diastereoisomers 1 and 2 3′-Fluoro-7-[(3-fluorophenyl)sulfonyl]-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran]

Step 1 3′-Fluoro-7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran]

As described for 7-iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] using 3-fluorotetrahydro-4H-pyran-4-one and 2-(6-iodo-benzofuran-3-yl)-ethylamine 2-methyldihydrofuran-3(2H)-one. 3-Fluorotetrahydro-4H-pyran-4-one was prepared as described in WO03/092586. MS m/z 388 [M+H]⁺.

Step 2

As described for 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (Example 22) starting from 3′-fluoro-7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran] and 3-fluorobenzenethiol The resulting diasteroisomeric mixture was separated using medium pressure liquid chromatography (140 g amine column) eluting with a gradient of EtOAc in hexanes (from 15% to 70% EtOAc).

Example 54 (Racemic diastereoisomer 1): mp 295-303° C. dec.; MS m/z 420 [M+H]⁺.

Example 55 (Racemic diastereoisomer 2): mp 251-260° C.; MS m/z 420 [M+H]⁺.

Examples 56 and 57 Racemic Diastereoisomers 1 and 2 7-[(3-Fluorophenyl)sulfonyl]-2′-methyl-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan]

Step 1 7-Iodo-2′-methyl-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan]

Prepared as described for 7-iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] using 2-(6-iodo-benzofuran-3-yl)-ethylamine and 2-methyldihydrofuran-3(2H)-one. The resulting diasteroisomeric mixture was separated using medium pressure liquid chromatography (140 g amine column) eluting with a gradient of EtOAc in hexanes (from 15% to 70% EtOAc).

Step 2

Prepared as described for 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (Example 22) starting from 3-fluorobenzenethiol and 7-iodo-2′-methyl-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan].

Racemic diastereoisomer 1: mp 295-303° C. dec.; MS m/z 370 [M+H]⁺.

Racemic diastereoisomer 2: mp 251-260° C.; MS m/z 370 [M+H]⁺.

Example 58 through Example 61 Chiral Diastereoisomers 7-[(3-Fluorophenyl)sulfonyl]-2′-methyl-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan]

The racemic diastereomers (Examples 54 and 55) were resolved by using SFC chiral separation (Chiralpak AD-H (3×15 cm with 40% EtOH/CO₂ at 100 bar). The four, chiral diastereomers were dissolved in 2 mL of diethyl ether containing 0.25 mL of 2.5 M ethanolic HCl. Trituration with ether afforded each of the 4 enantiomerically pure diasteromers as their HCl salts.

Example 58 (from racemic diastereoisomer 1): mp 262-265° C. dec.; MS m/z 402 [M+H]⁺.

Example 59 (from racemic diastereoisomer 2): mp 262-265° C.; MS m/z 402 [M+H]⁺.

Example 60 (from racemic diastereoisomer 1): mp 298-301° C. dec.; MS m/z 402 [M+H]⁺.

Example 61 (from racemic diastereoisomer 2): mp 298-301° C.; MS m/z 402 [M+H]⁺.

Example 62 4a-Methyl-6-(phenylsulfonyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine hydrochloride

Step 1 4a-Methyl-6-(phenylsulfanyl)-1,2,3,4,4a,9-hexahydro[1]benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Into a sealed tube was added tert-butyl 6-iodo-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P24 (0.491 g, 1.18 mmol), sodium tert-butoxide (341 mg, 3.55 mmol), copper (I) iodide (20 mg, 0.08 mmol), 1,2-ethanediol (132 μL, 2.38 mmol), N,N-dimethylformamide (17 mL, 210 mmol), and benzenethiol (123 μL, 1.19 mmol). The reaction was heated at 120° C. overnight. The reaction was concentrated and partitioned between DCM and water. The DCM layer was washed with brine, dried, filtered and concentrated under vacuum. The crude product was dissolved in DCM and purified on a 12 g silica gel column eluting with hexanes to 2:1 hexanes:ethyl acetate to give the product which was taken directly into the next step.

Step 2 4a-Methyl-6-(phenylsulfonyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine hydrochloride

To a solution of 4a-methyl-6-(phenylsulfanyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.327 g, 0.82 mmol) in methanol (10 mL, 0.2 mol) was added water (0.5 mL, 0.03 mol) and Oxone® (2.0 g, 0.0032 mol). The reaction was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in DCM and washed with brine, dried, filtered and concentrated. The crude product was purified on a 12 g silica gel column eluting with hexanes to 2:1 hexanes:ethyl acetate and then stirred in 4 M HCl in dioxane (5 mL, 0.04 mol) for 30 min. The product was precipitated by addition of DCM and ether. The solid was filtered, washed with ether and dried under house vacuum to afford the title compound. mp 236-238° C. dec.; MS m/z 330 [M+H]⁺. ¹H-NMR (400 MHz, DMSO): δ 1.45 (s, 3H), 1.75 (m, 1H), 1.90 (m, 1H), 2.82 (m, 1H), 3.03 (m, 1H), 3.35-3.56 (m, 2H), 4.63 (s, 1H), 7.08 (d, J=8.9 Hz, 1H), 7.58-7.70 (m, 3H), 7.81 (d, J=8.85 Hz, 1H), 7.91-7.96 (m, 3H), 8.91 (bs, 1H), 9.91 (bs, 1H).

The following examples were prepared essentially as described above. Example 103 and Example 104 were isolated from racemic mixture Example 100 and Example 105 and Example 106 were isolated from racemic mixture Example 101 using SFC chromatography on a chiral column as described in the general method. All compounds were isolated as the HCl salt unless otherwise specified.

Mp MS m/z Ex. # Name (° C.) [M + H]⁺ Stereochemistry Starting material 62 4a-methyl-6- 236-238 330 racemic benzenethiol (phenylsulfonyl)- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 63 7-({3-[(6-methylpyrazin-2- 128-130 424 racemic 3-[(6-methylpyrazin-2- yl)oxy]phenyl}sulfonyl)- yl)oxy]benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 64 7-[(2,6- 222-223 384 racemic 2,6-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 65 7-(1,3-benzothiazol-2- 195-196 373 racemic 1,3-benzothiazole-2-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 66 7-[(3-chloro-2- 188-189 364 racemic 3-chloro-2-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 67 7-(2,1,3-benzothiadiazol-4- 195-196 374 racemic 2,1,3-benzothiadiazole-4-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 68 7-[(1-methyl-1H-indol-4- 164-165 369 racemic 1-methyl-1H-indole-7-thiol yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 69 7-(1H-benzimidazol-2- 188-189 356 racemic 1H-benzimidazole-2-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 70 7-[(5-methyl-2,1,3- 200-201 388 racemic 5-methyl-2,1,3- benzothiadiazol-4- benzothiadiazole-4-thiol yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 71 7-[(5-methoxy-1,3- 222-223 403 racemic 5-methoxy-1,3-benzothiazole-2- benzothiazol-2-yl)sulfonyl]- thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 72 7-(2,1,3-benzoxadiazol-4- 189-190 358 racemic 2,1,3-benzoxadiazole-4-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 73 N-[3-(1,2,3,4,4a,9a- 228-229 373 racemic N-(3-sulfanylphenyl)acetamide hexahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl)phenyl]acetamide 74 7-{[3- 238-240 422 racemic 3-(benzyloxy)benzenethiol (benzyloxy)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 75 7-{[3-(1H-tetrazol-1- >300 384 racemic 3-(1H-tetrazol-1-yl)benzenethiol yl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 76 7-{[3-(benzyloxy)-5- 202-203 452 racemic 3-(benzyloxy)-5- methoxyphenyl]sulfonyl}- methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 77 7-{[3-methoxy-5-(propan-2- 233-234 404 racemic 3-methoxy-5-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 78 7-{[3-methoxy-5-(propan-2- 189-193 404 enantiomer 1 3-methoxy-5-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 79 7-{[3-methoxy-5-(propan-2- 188-190 404 enantiomer 2 3-methoxy-5-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 80 7-[(5-chloro-2- 258-259 378 5-chloro-2-methoxybenzenethiol methoxyphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 81 7-[(3-chloro-2- 245-246 366 3-chloro-2-fluorobenzenethiol fluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 82 7-[(3-chloro-2- 258-259 362 3-chloro-2-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 83 7-(2,1,3-benzothiadiazol-4- 242-243 372 2,1,3-benzothiadiazole-4-thiol ylsulfonyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 84 7-[(1-methyl-1H-indol-7- 224-225 367 1-methyl-1H-indole-7-thiol yl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 85 7-{[3-methoxy-5-(propan-2- 246-247 430 3-methoxy-5-(propan-2- yloxy)phenyl]sulfonyl}-4,4- yloxy)benzenethiol dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 86 7-[(3-fluorophenyl)sulfonyl]- 291-293 360 3-fluorobenzenethiol 4,4-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 87 4,4-dimethyl-7-{[3-(propan- 251-252 400 3-(propan-2-yloxy)benzenethiol 2-yloxy)phenyl]sulfonyl}- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 88 6-[(2,3- 216-217 414 racemic 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]-7- methoxy-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 89 6-[(3-fluorophenyl)sulfonyl]- 197-204 364 racemic 3-fluorobenzenethiol 7-methoxy-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 90 6-[(3-fluorophenyl)sulfonyl]- 168-171 348 racemic 3-fluorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 91 4a-methyl-6-(pyridin-2- 255-257 331 racemic pyridine-2-thiol ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 92 6-[(4-fluorophenyl)sulfonyl]- 163-165 348 racemic 4-fluorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 93 6-[(2,4- 215-216 366 racemic 2,4-difluorobenzenethiol difluorophenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 94 6-[(3,5- 196-198 366 racemic 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 95 6-[(3-fluoro-4- 185-187 378 racemic 3-fluoro-4- methoxyphenyl)sulfonyl]-4a- methoxybenzenethiol methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 96 N-(4-{[4a-methyl- 212-214 387 racemic N-(4- 1,2,3,4,4a,9a- sulfanylphenyl)acetamide hexahydro[1]benzofuro[2,3- c]pyridin-6- yl]sulfonyl}phenyl)acetamide 97 (2-{[4a-methyl- 204-206 360 racemic (2- 1,2,3,4,4a,9a- sulfanylphenyl)methanol hexahydro[1]benzofuro[2,3- c]pyridin-6- yl]sulfonyl}phenyl)methanol 98 4a-methyl-6-{[3-(propan-2- 162-164 388 racemic 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 99 6-[(2-fluorophenyl)sulfonyl]- 260-262 348 racemic 2-fluorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 100 6-[(3-chlorophenyl)sulfonyl]- 160-162 364 racemic 2-chlorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 101 6-[(2,3- 210-212 398 racemic 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 102 7-[(3-fluorophenyl)sulfonyl]- >300 346 racemic 3-fluorobenzenethiol 4-methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 103 6-[(3-chlorophenyl)sulfonyl]- 218-220 364 enantiomer 1 2-chlorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 104 6-[(3-chlorophenyl)sulfonyl]- 216-218 364 enantiomer 2 2-chlorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 105 6-[(2,3- 242-244 398 enantiomer 1 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 106 6-[(2,3- 244-246 398 enantiomer 2 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 107 7-(3,5-Difluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride

Step 1 7-(3,5-Difluoro-phenylsulfanyl)-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Anhydrous DMF was sparged with argon gas for 1 h before being used. 560 μL of a 0.625 M stock solution of 7-iodo-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester P08 (120 mg, 0.300 mmol) in DMF, 300 μL of a 0.10 M stock solution of neocuproine (6.2 mg, 0.030 mmol) in DMF and 580 μL of a 0.310 M stock solution of copper (I) iodide (34 mg, 0.180 mmol) in DMF were added sequentially into a reaction vial. 3,5-Difluorobenzenethiol (96.5 μL, 0.660 mmol, 2.2 eq) was added neat followed by 630 μL of a 1.0 M stock solution of sodium tert-butoxide (60.5 mg, 0.630 mmol) in DMF. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The residue was suspended into DCE:MeOH 95:5 (2.0 mL), passed through a silica gel column (1 g) and eluted with DCE:MeOH 95:5 (3×2.0 mL). The eluent was concentrated to yield crude 7-(3,5-difluoro-phenylsulfanyl)-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester which was used in the next step without further purification.

Step 2 7-(3,5-Difluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride

7-(3,5-Difluoro-phenylsulfanyl)-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.30 mmol, 1.0 eq) was suspended into DCE (1 mL). A 1.0 M solution of m-CPBA (70% from ACROS) in DCE (4.0 eq) was added slowly. The reaction solution was shaken for 10 min and diluted with DCE (2.0 mL) followed by addition of 1N aqueous NaOH (2 mL). The mixture was shaken, centrifugated and the aqueous layer was removed. The organic solution was then washed with 1N aqueous NaOH (2 mL) twice and H₂O (2 mL) once. The organic layer was then transferred into a new glass tube and the solvent was evaporated. The resulting oil was dissolved in a 1:1 mixture of TFA:DCM. (2.0 mL). The solution was shaken for 30 min and then concentrated. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. The product was redissolved into a small amount of DCM and treated with 1.0 N HCl in diethyl ether to afford 7-(3,5-difluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride. MS m/z 350 [M+H]⁺

The following examples were prepared essentially as described above.

Ex. MS m/z Stereo- # Name [M + H]⁺ chemistry Salt Starting material 107 7-[(3,5- 350 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 108 (1S)-7-(phenylsulfonyl)- 370 enantiomer 1 HCl benzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 109 (1S)-7-[(2,5- 406 enantiomer 1 HCl 2,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 110 (1R)-7-(phenylsulfonyl)- 370 enantiomer 2 HCl benzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 111 (1R)-7-[(2,5- 406 enantiomer 1 HCl 2,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 112 7-[(3-chlorophenyl)sulfonyl]- 350 racemic HCl 3-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 113 7-[(2-chlorophenyl)sulfonyl]- 350 racemic HCl 2-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 114 7-(naphthalen-1-ylsulfonyl)- 366 racemic HCl naphthalene-1-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 115 7-[(3,4- 376 racemic HCl 3,4-dimethoxybenzenethiol dimethoxyphenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 116 7-[(4-phenoxyphenyl)sulfonyl]- 408 racemic HCl 4-phenoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 117 7-[(3-fluorophenyl)sulfonyl]- 334 racemic TFA 3-fluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 118 7-[(3-methoxyphenyl)sulfonyl]- 346 racemic TFA 3-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 119 7-(2,3-dihydro-1,4- 374 racemic TFA 2,3-dihydro-1,4-benzodioxine- benzodioxin-6-ylsulfonyl)- 6-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 120 7-[(3,4- 384 racemic TFA 3,4-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 121 7-[(4-methylphenyl)sulfonyl]- 330 racemic TFA 4-methylbenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 122 7-(naphthalen-2-ylsulfonyl)- 366 racemic TFA naphthalene-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 123 7-[(2,3- 384 racemic TFA 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 124 7-[(4-nitrophenyl)sulfonyl]- 361 racemic TFA 4-nitrobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 125 7-{[4-(propan-2- 358 racemic TFA 4-(propan-2-yl)benzenethiol yl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 126 7-{[3- 384 racemic HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 127 7-[(3-chloro-4- 368 racemic HCl 3-chloro-4-fluorobenzenethiol fluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 128 7-[(3,4- 352 racemic HCl 3,4-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 129 7-[(3-fluoro-4- 364 racemic HCl 3-fluoro-4- methoxyphenyl)sulfonyl]- methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 130 7-[(5-fluoro-2- 348 racemic HCl 5-fluoro-2-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 131 7-[(3,5- 352 racemic HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 132 7-[(5-fluoro-2- 364 racemic HCl 5-fluoro-2- methoxyphenyl)sulfonyl]- methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 133 7-[(3-bromophenyl)sulfonyl]- 394 racemic HCl 3-bromobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 134 7-[(4-fluorophenyl)sulfonyl]- 334 racemic HCl 4-fluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 135 7-[(2,5- 368 racemic HCl 2,5-dichlorobenzenethiol dichlorophenyl)sulfinyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 136 7-{[3-(propan-2- 374 racemic HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 137 7-[(4-fluoro-3- 348 racemic HCl 4-fluoro-3-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 138 methyl 3-[1,2,3,4,4a,9a- 374 racemic HCl methyl 3-sulfanylbenzoate hexahydro[1]benzofuro[2,3- c]pyridin-7-ylsulfonyl]benzoate 139 4-[1,2,3,4,4a,9a- 341 racemic HCl 4-sulfanylbenzonitrile hexahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl]benzonitrile 140 N-{4-[1,2,3,4,4a,9a- 373 racemic HCl N-(4- hexahydro[1]benzofuro[2,3- sulfanylphenyl)acetamide c]pyridin-7- ylsulfonyl]phenyl}acetamide 141 7-[(3-methylphenyl)sulfonyl]- 330 racemic HCl 3-methylbenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 142 7-[(2,5-difluorophenyl)sulfinyl]- 336 racemic HCl 2,5-difluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 143 7-[(2,5- 352 racemic HCl 2,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 144 7-[(2,3,5,6- 372 racemic HCl 2,3,5,6- tetrafluorophenyl)sulfinyl]- tetrafluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 145 7-(biphenyl-4-ylsulfonyl)- 392 racemic HCl biphenyl-4-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 146 7-[(2-fluorophenyl)sulfonyl]- 334 racemic HCl 2-fluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 147 7-[(3-chloro-5- 368 racemic HCl 3-chloro-5-fluorobenzenethiol fluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 148 7-{[4-chloro-3- 418 racemic HCl 4-chloro-3- (trifluoromethyl)phenyl]sulfonyl}- (trifluoromethyl)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 149 7-{[3- 400 racemic HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 150 7-[(2,3,5,6- 388 racemic HCl 2,3,5,6- tetrafluorophenyl)sulfonyl]- tetrafluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 151 7-{[4- 384 racemic HCl 4- (trifluoromethyl)phenyl]sulfonyl}- (trifluoromethyl)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 152 7-(biphenyl-2-ylsulfonyl)- 392 racemic HCl biphenyl-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 153 7-(biphenyl-2-ylsulfonyl)- 392 racemic HCl biphenyl-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 154 7-(cyclohexylsulfonyl)- 322 racemic HCl cyclohexanethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 155 7-[(3,5- 384 racemic HCl 3,5-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 156 7-[(2,3- 384 enantiomer 1 HCl 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 157 7-[(3-chloro-5- 368 enantiomer 1 HCl 3-chloro-5-fluorobenzenethiol fluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 158 7-[(3,5- 352 enantiomer 1 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 159 7-{[3-(propan-2- 374 enantiomer 1 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 160 7-{[3- 400 enantiomer 1 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 161 7-{[3- 384 enantiomer 1 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 162 7-[(2,3- 384 enantiomer 2 HCl 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 163 7-[(3-chloro-5- 368 enantiomer 2 HCl 3-chloro-5-fluorobenzenethiol fluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 164 7-[(3,5- 352 enantiomer 2 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 165 7-{[3-(propan-2- 374 enantiomer 2 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 166 7-{[3- 400 enantiomer 2 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 167 7-{[3- 384 enantiomer 2 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 168 6-[(3-fluorophenyl)sulfonyl]- 334 racemic HCl 3-fluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 169 6-[(2-chlorophenyl)sulfonyl]- 350 racemic HCl 2-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 170 6-(naphthalen-1-ylsulfonyl)- 366 racemic HCl naphthalene-1-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 171 6-[(3,4- 376 racemic HCl 3,4-dimethoxybenzenethiol dimethoxyphenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 172 6-[(3,4- 384 racemic HCl 3,4-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 173 6-[(4-phenoxyphenyl)sulfonyl]- 408 racemic HCl 4-phenoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 174 6-[(4-methylphenyl)sulfonyl]- 330 racemic HCl 4-methylbenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 175 6-(naphthalen-2-ylsulfonyl)- 366 racemic HCl naphthalene-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 176 6-[(2,3- 384 racemic HCl 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 177 6-[(4-nitrophenyl)sulfonyl]- 361 racemic HCl 4-nitrobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 178 6-[(3-methoxyphenyl)sulfonyl]- 346 racemic TFA 3-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 179 6-{[4-(propan-2- 358 racemic TFA 4-(propan-2-yl)benzenethiol yl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 180 6-(2,3-dihydro-1,4- 374 racemic TFA 2,3-dihydro-1,4-benzodioxine- benzodioxin-6-ylsulfonyl)- 6-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 181 6-(phenylsulfonyl)- 316 racemic TFA benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 182 8-[(3-methoxyphenyl)sulfonyl]- 346 racemic TFA 3-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 183 8-[(2-chlorophenyl)sulfonyl]- 350 racemic TFA 2-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 184 8-(naphthalen-1-ylsulfonyl)- 366 racemic TFA naphthalene-1-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 185 8-(2,3-dihydro-1,4- 374 racemic TFA 2,3-dihydro-1,4-benzodioxine- benzodioxin-6-ylsulfonyl)- 6-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 186 8-[(3,4- 384 racemic TFA 3,4-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 187 8-[(4-methoxyphenyl)sulfonyl]- 346 racemic TFA 4-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 188 8-[(4-chlorophenyl)sulfonyl]- 350 racemic TFA 4-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 189 8-(naphthalen-2-ylsulfonyl)- 366 racemic TFA naphthalene-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 190 8-[(4-nitrophenyl)sulfonyl]- 361 racemic TFA 4-nitrobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 191 8-(biphenyl-2-ylsulfonyl)- 392 racemic TFA biphenyl-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 192 7-{[3- 382 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 193 7-[(3-chloro-4- 366 HCl 3-chloro-4-fluorobenzenethiol fluorophenyl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 194 7-[(3-fluoro-4- 362 HCl 3-fluoro-4- methoxyphenyl)sulfonyl]- methoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 195 7-{[4-(propan-2- 356 HCl 4-(propan-2-yl)benzenethiol yl)phenyl]sulfonyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 196 7-[(2,3- 381 HCl 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 197 7-[(3,4- 381 HCl 3,4-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 198 7-[(4-methoxyphenyl)sulfonyl]- 344 HCl 4-methoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 199 7-[(3-methoxyphenyl)sulfonyl]- 344 HCl 3-methoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 200 7-(2,3-dihydro-1,4- 372 HCl 2,3-dihydro-1,4-benzodioxine- benzodioxin-6-ylsulfonyl)- 6-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 201 7-[(4-phenoxyphenyl)sulfonyl]- 406 HCl 4-phenoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 202 7-(naphthalen-1-ylsulfonyl)- 364 HCl naphthalene-1-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 203 7-[(4-chlorophenyl)sulfonyl]- 348 HCl 4-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 204 7-[(4-methylphenyl)sulfonyl]- 328 HCl 4-methylbenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 205 7-[(4-nitrophenyl)sulfonyl]- 359 HCl 4-nitrobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 206 7-[(5-fluoro-2- 346 HCl 5-fluoro-2-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 207 7-[(3-chloro-5- 366 HCl 3-chloro-5-fluorobenzenethiol fluorophenyl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 208 7-[(3,5- 350 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 209 7-{[4-chloro-3- 400 racemic HCl 4-chloro-3- (trifluoromethyl)phenyl]sulfinyl}- (trifluoromethyl)benzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 210 7-{[4-chloro-3- 416 HCl 4-chloro-3- (trifluoromethyl)phenyl]sulfonyl}- (trifluoromethyl)benzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 211 7-[(3,5- 381 HCl 3,5-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 212 7-[(3-bromophenyl)sulfonyl]- 391 HCl 3-bromobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 213 7-[(4-fluorophenyl)sulfonyl]- 332 HCl 4-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 214 7-[(2,5- 366 racemic HCl 2,5-dichlorobenzenethiol dichlorophenyl)sulfinyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 215 7-[(2,5- 381 HCl 2,5-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 216 7-{[3-(propan-2- 356 racemic HCl 3-(propan-2- yloxy)phenyl]sulfinyl}-1,2,3,4- yloxy)benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine 217 7-{[3-(propan-2- 372 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}-1,2,3,4- yloxy)benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine 218 7-[(4-fluoro-3- 346 HCl 4-fluoro-3-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 219 methyl 3-(1,2,3,4- 372 HCl methyl 3-sulfanylbenzoate tetrahydro[1]benzofuro[2,3- c]pyridin-7-ylsulfonyl)benzoate 220 4-(1,2,3,4- 339 HCl 4-sulfanylbenzonitrile tetrahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl)benzonitrile 221 7-[(3-methylphenyl)sulfonyl]- 328 HCl 3-methylbenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 222 7-[(2,5-difluorophenyl)sulfinyl]- 334 racemic HCl 2,5-difluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 223 7-[(2,5- 350 HCl 2,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 224 7-[(2,3,5,6- 370 racemic HCl 2,3,5,6- tetrafluorophenyl)sulfinyl]- tetrafluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 225 7-[(2,3,5,6- 386 HCl 2,3,5,6- tetrafluorophenyl)sulfonyl]- tetrafluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 226 7-{[4- 382 racemic HCl 4- (trifluoromethoxy)phenyl]sulfi- (trifluoromethoxy)benzenethiol nyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 227 7-{[4- 398 HCl 4- (trifluoromethoxy)phenyl]sulfo- (trifluoromethoxy)benzenethiol nyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 228 7-(biphenyl-4-ylsulfonyl)- 390 HCl biphenyl-4-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 229 7-[(2-chlorophenyl)sulfinyl]- 332 racemic HCl 2-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 230 7-[(2-chlorophenyl)sulfonyl]- 348 HCl 2-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 231 7-[(2-fluorophenyl)sulfonyl]- 332 HCl 2-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 232 7-(biphenyl-2-ylsulfonyl)- 390 HCl biphenyl-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 233 7-(cyclohexylsulfonyl)-1,2,3,4- 320 HCl cyclohexanethiol tetrahydro[1]benzofuro[2,3- c]pyridine 234 7-(propan-2-ylsulfonyl)- 280 HCl propane-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 235 1-methyl-7-(phenylsulfonyl)- 328 HCl benzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 236 7-[(3-fluoro-4- 376 racemic HCl 3-fluoro-4- methoxyphenyl)sulfonyl]-1- methoxybenzenethiol methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 237 1-methyl-7-{[3- 396 racemic HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 238 7-[(3,4- 364 racemic HCl 3,4-difluorobenzenethiol difluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 239 6-{[3- 382 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 240 6-[(3,4- 350 HCl 3,4-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 241 6-[(3-fluoro-4- 362 HCl 3-fluoro-4- methoxyphenyl)sulfonyl]- methoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 242 6-[(3,4- 374 HCl 3,4-dimethoxybenzenethiol dimethoxyphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 243 6-[(3-chlorophenyl)sulfonyl]- 348 HCl 3-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 244 6-[(3-fluorophenyl)sulfonyl]- 332 HCl 3-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 245 6-[(4-methoxyphenyl)sulfonyl]- 344 HCl 4-methoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 246 6-[(3-methoxyphenyl)sulfonyl]- 344 HCl 3-methoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 247 6-(2,3-dihydro-1,4- 372 HCl 2,3-dihydro-1,4-benzodioxine- benzodioxin-6-ylsulfonyl)- 6-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 248 6-[(4-phenoxyphenyl)sulfonyl]- 406 HCl 4-phenoxybenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 249 6-(naphthalen-1-ylsulfonyl)- 364 HCl naphthalene-1-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 250 6-[(4-chlorophenyl)sulfonyl]- 348 HCl 4-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 251 6-(naphthalen-2-ylsulfonyl)- 364 HCl naphthalene-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 252 6-[(4-methylphenyl)sulfonyl]- 328 HCl 4-methylbenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 253 6-[(4-nitrophenyl)sulfonyl]- 359 HCl 4-nitrobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 254 6-[(5-fluoro-2- 346 HCl 5-fluoro-2-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 255 6-[(3-chloro-5- 366 HCl 3-chloro-5-fluorobenzenethiol fluorophenyl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 256 6-[(3,5- 350 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 257 6-{[4-chloro-3- 416 HCl 4-chloro-3- (trifluoromethyl)phenyl]sulfonyl}- (trifluoromethyl)benzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 258 6-[(3-chloro-4- 366 HCl 3-chloro-4-fluorobenzenethiol fluorophenyl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 259 6-{[4-(propan-2- 356 HCl 4-(propan-2-yl)benzenethiol yl)phenyl]sulfonyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 260 6-[(2,3- 381 HCl 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 261 6-[(3,4- 381 HCl 3,4-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 262 6-[(3,5- 381 HCl 3,5-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 263 6-[(3-bromophenyl)sulfonyl]- 391 HCl 3-bromobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 264 6-[(4-fluorophenyl)sulfonyl]- 332 HCl 4-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 265 6-[(4-fluorophenyl)sulfonyl]- 332 HCl 4-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 266 6-[(2,5- 381 HCl 2,5-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 267 6-{[3-(propan-2- 372 HCl 3-(propan-2- yloxy)phenyl]sulfonyl}-1,2,3,4- yloxy)benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine 268 6-[(4-fluoro-3- 346 HCl 4-fluoro-3-methylbenzenethiol methylphenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 269 methyl 3-(1,2,3,4- 372 HCl methyl 3-sulfanylbenzoate tetrahydro[1]benzofuro[2,3- c]pyridin-6-ylsulfonyl)benzoate 270 6-{[3- 398 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 271 4-(1,2,3,4- 339 HCl 4-sulfanylbenzonitrile tetrahydro[1]benzofuro[2,3- c]pyridin-6- ylsulfonyl)benzonitrile 272 N-[4-(1,2,3,4- 371 HCl N-(4- tetrahydro[1]benzofuro[2,3- sulfanylphenyl)acetamide c]pyridin-6- ylsulfonyl)phenyl]acetamide 273 6-[(2,5- 350 HCl 2,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 274 6-[(2,3,5,6- 386 HCl 2,3,5,6- tetrafluorophenyl)sulfonyl]- tetrafluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 275 6-{[4- 398 HCl 4- (trifluoromethoxy)phenyl]sulfo- (trifluoromethoxy)benzenethiol nyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 276 6-[(2-chlorophenyl)sulfonyl]- 348 HCl 2-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 277 6-[(2-fluorophenyl)sulfonyl]- 332 HCl 2-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 278 6-{[4- 382 HCl 4- (trifluoromethyl)phenyl]sulfonyl}- (trifluoromethyl)benzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 279 6-(biphenyl-2-ylsulfinyl)- 374 racemic HCl biphenyl-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 280 6-(cyclohexylsulfonyl)-1,2,3,4- 320 HCl cyclohexanethiol tetrahydro[1]benzofuro[2,3- c]pyridine 281 6-(propan-2-ylsulfonyl)- 280 HCl propane-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 282 1-methyl-6-{[3- 396 racemic HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 283 6-[(3-fluorophenyl)sulfonyl]-1 - 346 racemic HCl 3-fluorobenzenethiol methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 284 6-[(3,4- 364 racemic HCl 3,4-difluorobenzenethiol difluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 285 6-[(3-fluoro-4- 376 racemic HCl 3-fluoro-4- methoxyphenyl)sulfonyl]-1- methoxybenzenethiol methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 286 4,4-dimethyl-7- 342 HCl benzenethiol (phenylsulfonyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 287 7-[(3,5- 378 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]-4,4- dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 288 7-[(3-fluoro-4- 390 HCl 3-fluoro-4- methoxyphenyl)sulfonyl]-1,1- methoxybenzenethiol dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 289 1,1-dimethyl-7-{[3- 410 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 290 7-[(3,4- 378 HCl 3,4-difluorobenzenethiol difluorophenyl)sulfonyl]-1,1- dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 291 1,1-dimethyl-7-{[3- 426 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 292 1,1-dimethyl-7- 342 TFA benzenethiol (phenylsulfonyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 293 7-[(3,5- 378 TFA 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]-1,1- dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 294 6-[(3-chlorophenyl)sulfonyl]- 350 racemic TFA 3-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 294 6-[(3-Chlorophenyl)sulfonyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine trifluoroacetic acid salt

Step 1 6-(3-Chlorophenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Anhydrous DMF was sparged with argon gas for 1 h before being used. 6-Iodo-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (80.25 mg, 0.200 mmol) was dissolved into anhydrous DMF (2.50 mL) in a one dram vial. The sodium tert-butoxide (58 mg, 0.60 mmol), neocuproine (4.2 mg, 0.020 mmol) and copper (I) iodide (11 mg, 0.060 mmol) were added sequentially at room temperature. 3-Chlorobenzenethiol (63.6 mg, 0.440 mmol) was added neat last. The reaction was shaken at 110° C. overnight. It was cooled to room temperature and concentrated. The residue was partially dissolved into a 2% MeOH in DCM solvent mixture (2.0 mL) with sonication. Silica gel (˜55 mg) was added into a filter plate. The suspension of product was flushed through the dry silica gel using 2% MeOH in DCM. The eluent was then concentrated to yield crude 6-(3-chlorophenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester which was used in the next step without further purification. MS m/z 418 [M+H]⁺

Step 2 6-(3-Chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

6-(3-Chlorophenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (83.6 mg, 0.20 mmol, 1.0 eq) was dissolved into DCM (1 mL). To this was added 70% m-Chloroperbenzoic acid (120 mg, 0.50 mmol) in one portion at room temperature. The reaction was shaken at room temperature for 2 h and then concentrated. The crude product, 6-(3-chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester was taken on to the next step without further purification. MS m/z 472 [M+Na]⁺

Step 3 6-[(3-Chlorophenyl)sulfonyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine trifluoroacetic acid salt

6-(3-Chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.20 mmol, 1.0 eq) was dissolved into 20% TFA in DCM and shaken at room temperature for 3 h. The reaction solution was then concentrated and the crude product purified by preparative LC/MS to afford 6-[(3-chlorophenyl)sulfonyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine as a trifluoroacetic acid salt. MS m/z 350 [M+H]⁺

The following examples were prepared essentially as described above. Example 360 and Example 361 were isolated from racemic mixture Example 100, and Example 362 and Example 363 were isolated from racemic mixture Example 101 using SFC chromatography on a chiral column as described in the general method.

Ex. MS m/z Stereo- # Name [M + H]⁺ chemistry Salt Starting material 294 6-[(3-chlorophenyl)sulfonyl]- 350 racemic TFA 3-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 295 4,4-dimethyl-7- 398 racemic HCl benzenethiol (phenylsulfonyl)-3,4,4′,5′- tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine-1,3′- furan] 296 7-(phenylsulfonyl)- 384 HCl benzenethiol 2′,3,3′,4,5′,6′-hexahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 297 7-{[3- 436 racemic HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfinyl}- 2′,3,3′,4,5′,6′-hexahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 298 7-{[3- 452 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 2′,3,3′,4,5′,6′-hexahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 299 7-{[3- 452 racemic HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfi- nyl}-2′,3,3′,4,5′,6′-hexahydro- 2H-spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 300 7-{[3- 468 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-2′,3,3′,4,5′,6′-hexahydro- 2H-spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 301 7-[(3,5- 420 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 2′,3,3′,4,5′,6′-hexahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran] 302 7-[(3,5- 406 enantiomer 1 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 303 (7-[(3-chlorophenyl)sulfonyl]- 404 enantiomer 1 HCl 3-chlorobenzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 304 7-{[3- 438 enantiomer 1 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 305 7-[(3,5- 406 enantiomer 2 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 306 7-[(3-chlorophenyl)sulfonyl]- 404 enantiomer 2 HCl 3-chlorobenzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 307 7-{[3- 438 enantiomer 2 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 308 6-{[3-fluorophenyl]sulfonyl}- 388 racemate 3-fluorobenzenethiol 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 309 6-{[3- 438 racemate 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 310 6-{[3,5- 406 racemate 3,5-difluorobenzenethiol difluorophenyl]sulfonyl}- 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan] 311 7-(phenylsulfonyl)- 384 enantiomer 1 HCl benzenethiol 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 312 7-[(3,5- 419 enantiomer 1 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 313 7-{[3- 468 enantiomer 1 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-2,3,4,5′,6′,9-hexahydro- 4′H-spiro[beta-carboline-1,3′- pyran] 314 7-{[3- 452 enantiomer 1 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 315 7-(phenylsulfonyl)- 384 enantiomer 2 HCl benzenethiol 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 316 7-[(3-chlorophenyl)sulfonyl]- 418 enantiomer 2 HCl 3-chlorobenzenethiol 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 317 (7-[(3-fluorophenyl)sulfonyl]- 402 enantiomer 2 HCl 3-difluorobenzenethiol 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 318 7-[(3,5- 420 enantiomer 2 HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]- 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 319 7-{[3- 468 enantiomer 2 HCl 3-(trifluoromethoxy)benzenethiol (trifluoromethoxy)phenyl]sulfo- nyl}-2,3,4,5′,6′,9-hexahydro- 4′H-spiro[beta-carboline-1,3′- pyran] 320 7-{[3- 452 enantiomer 2 HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 2,3,4,5′,6′,9-hexahydro-4′H- spiro[beta-carboline-1,3′- pyran] 321 7-(phenylsulfonyl)- 316 racemic TFA benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 322 7-[(4-chlorophenyl)sulfonyl]- 350 racemic TFA 4-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 323 7-[(4-methoxyphenyl)sulfonyl]- 346 racemic TFA 4-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 324 7-(phenylsulfonyl)- 316 racemic HCl benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 325 7-[(4-methoxyphenyl)sulfonyl]- 346 racemic HCl 4-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 326 7-(phenylsulfonyl)- 316 racemic HCl benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 327 7-[(6-methylpyridin-2- 315 racemic HCl 6-methylpyridine-2-thiol yl)sulfinyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 328 7-[(6-methylpyridin-2- 331 racemic HCl 6-methylpyridine-2-thiol yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 329 7-[(1-oxidopyridin-4- 333 racemic HCl pyridine-4-thiol yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 330 7-(pyridin-4-ylsulfonyl)- 317 racemic HCl pyridine-4-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 331 7-(pyridin-2-ylsulfonyl)- 317 racemic HCl pyridine-2-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 332 7-(quinolin-8-ylsulfonyl)- 367 racemic HCl quinoline-8-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 333 7-(quinolin-8-ylsulfonyl)- 367 racemic HCl quinoline-8-thiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 334 6-(phenylsulfonyl)- 316 Racemic HCl benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 335 6-[(4-chlorophenyl)sulfonyl]- 350 racemic TFA 4-chlorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 336 6-[(4-methoxyphenyl)sulfonyl]- 346 racemic TFA 4-methoxybenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 337 6-(phenylsulfonyl)- 316 Racemic HCl benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 338 8-[(2,3- 384 racemic TFA 2,3-dichlorobenzenethiol dichlorophenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 339 7-(phenylsulfonyl)-1,2,3,4- 314 TFA benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine 340 7-[(3-chlorophenyl)sulfonyl]- 348 HCl 3-chlorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 341 7-[(3-fluorophenyl)sulfonyl]- 332 HCl 3-fluorobenzenethiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 342 3-(1,2,3,4- 329 HCl 3-aminobenzenethiol tetrahydro[1]benzofuro[2,3- c]pyridin-7-ylsulfonyl)aniline 343 7-[(6-methylpyridin-2- 329 HCl 6-methylpyridine-2-thiol yl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 344 7-(pyridin-4-ylsulfonyl)- 315 HCl pyridine-4-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 345 7-(pyridin-2-ylsulfonyl)- 315 HCl pyridine-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 346 7-(quinolin-8-ylsulfonyl)- 365 HCl quinoline-8-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 347 N,N-dimethyl-3-(1,2,3,4- 357 HCl 3-(dimethylamino)benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridin-7-ylsulfonyl)aniline 348 6-(phenylsulfonyl)-1,2,3,4- 314 HCl benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine 349 3-(1,2,3,4- 329 HCl 3-aminobenzenethiol tetrahydro[1]benzofuro[2,3- c]pyridin-6-ylsulfonyl)aniline 350 6-[(6-methylpyridin-2- 329 HCl 6-methylpyridine-2-thiol yl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 351 6-[(1-oxidopyridin-4- 331 HCl pyridine-4-thiol yl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 352 6-(pyridin-4-ylsulfonyl)- 315 HCl pyridine-4-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 353 6-(pyridin-2-ylsulfonyl)- 315 HCl pyridine-2-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 354 6-(quinolin-8-ylsulfonyl)- 365 HCl quinoline-8-thiol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 355 N,N-dimethyl-3-(1,2,3,4- 357 HCl 3-(dimethylamino)benzenethiol tetrahydro[1]benzofuro[2,3- c]pyridin-6-ylsulfonyl)aniline 356 7-[(4-fluorophenyl)sulfonyl]- 348 racemic HCl 4-fluorobenzenethiol 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 357 4a-methyl-7-{[3- 398 racemic HCl 3-(trifluoromethyl)benzenethiol (trifluoromethyl)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 358 4a-methyl-7-{[3- 414 racemic HCl 3-(trifluoromethoxy)benzene- (trifluoromethoxy)phenyl]sulfo- thiol nyl}-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 359 7-[(3,5- 366 racemic HCl 3,5-difluorobenzenethiol difluorophenyl)sulfonyl]-4a- methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 360 7-[(3-fluorophenyl)sulfonyl]- 334 Eantiomer 1 HCl 3-fluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 361 7-[(3-fluorophenyl)sulfonyl]- 334 Eantiomer 2 HCl 3-fluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 362 7-(phenylsulfonyl)- 316 Eantiomer 1 HCl benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 363 7-(phenylsulfonyl)- 316 Eantiomer 2 HCl benzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 364 7-(3-Fluoro-5-isopropoxy-benzenesulfonyl)-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride (Enantiomer 1)

Step 1 7-(3-Fluoro-5-isopropoxy-phenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Anhydrous DMF was sparged with argon gas for 1 h before being used. 600 μL (0.30 mmol) of a 0.5 M stock solution of 7-triisopropylsilanylsulfanyl-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (enantiomer 1) in DMF was introduced into a one dram vial containing neocuproine (6.25 mg, 0.03 mmol) and copper (I) iodide (20.0 mg, 0.10 mmol). DMF (900 μL), 3-fluoro-5-isopropoxy-iodobenzene (0.45 mmol, 1.5 eq) and cesium fluoride (50.1 mg, 0.33 mmol) were added sequentially. The reaction mixture was shaken at 90° C. for 3 h and then concentrated. The residual solid was suspended into DCE:MeOH 95:5 (2.0 mL), passed through a silica gel column (1 g), eluted with DCE:MeOH 95:5 (3×2.0 mL). The combined eluent was concentrated to provide crude 7-(3-fluoro-5-isopropoxy-phenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester which was used in the next step without further purification. MS m/z 460 [M+H]⁺

Step 2 7-(3-Fluoro-5-isopropoxy-benzenesulfonyl)-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride

7-(3-Fluoro-5-isopropoxy-phenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester was suspended into DCE (1.0 mL). A 0.5 M solution of m-CPBA (70% from ACROS) in DCE (4.0 eq) was added slowly. The reaction solution was shaken for 10 minutes and diluted with DCE (2.0 mL). 1N aqueous NaOH (2 mL) was added, the mixture was shaken, centrifugated and the aqueous layer removed. The organic solution was then washed with 1N aqueous NaOH (2 mL) twice and H₂O (2 mL) once. The organic layer was transferred into a new glass tube and the solvent was evaporated. The resulting oil was dissolved in a 1:1 mixture of TFA:DCM. (2.0 mL). This solution was shaken for 30 min and then concentrated. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. The product was redissolved into a small amount of DCM and treated with 1.0 N HCl in diethyl ether to afford 7-(3-fluoro-5-isopropoxy-benzenesulfonyl)-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride. MS m/z 392 [M+H]⁺.

The following examples were prepared essentially as described above.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 364 7-{[3-fluoro-5-(propan-2- 392 enantiomer 1 HCl 1-fluoro-3-iodo-5- yloxy)phenyl]sulfonyl}- (propan-2-yloxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 365 7-[(2,3-difluorophenyl)sulfonyl]- 378 TFA 1,2-difluoro-3- 1,1-dimethyl-1,2,3,4- iodobenzene tetrahydro[1]benzofuro[2,3- c]pyridine 366 4-[(1,1-dimethyl-1,2,3,4- 359 TFA 4-iodopyridin-2(1H)-one tetrahydro[1]benzofuro[2,3- c]pyridin-7-yl)sulfonyl]pyridin- 2(1H)-one 367 7-[(5-bromopyridin-3- 421 TFA 3-bromo-5-iodopyridine yl)sulfonyl]-1,1-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 368 1,1-dimethyl-7-{[2-(morpholin-4- 428 TFA 4-(3-iodopyridin-2- yl)pyridin-3-yl]sulfonyl}-1,2,3,4- yl)morpholine tetrahydro[1]benzofuro[2,3- c]pyridine 369 7-[(5-methoxy-1-oxidopyridin-3- 389 TFA 3-iodo-5-methoxypyridine yl)sulfonyl]-1,1-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 370 7-[(5-methoxypyridin-3- 373 TFA 3-iodo-5-methoxypyridine yl)sulfonyl]-1,1-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 371 5-chloro-3-[(1,1-dimethyl- 408 TFA 5-chloro-3-iodopyridin-2- 1,2,3,4- amine tetrahydro[1]benzofuro[2,3- c]pyridin-7-yl)sulfonyl]pyridin-2- amine 1-oxide 372 5-chloro-3-[(1,1-dimethyl- 392 TFA 5-chloro-3-iodopyridin-2- 1,2,3,4- amine tetrahydro[1]benzofuro[2,3- c]pyridin-7-yl)sulfonyl]pyridin-2- amine 373 5-chloro-3-[(1,1-dimethyl- 393 TFA 5-chloro-3-iodopyridin-2- 1,2,3,4- ol tetrahydro[1]benzofuro[2,3- c]pyridin-7-yl)sulfonyl]pyridin-2- ol 374 1,1-dimethyl-7-[(2-methyl-1- 373 TFA 3-iodo-2-methylpyridine oxidopyridin-3-yl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 375 1,1-dimethyl-7-[(2- 357 TFA 3-iodo-2-methylpyridine methylpyridin-3-yl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 376 7-[(5-chloropyridin-3- 377 TFA 3-chloro-5-iodopyridine yl)sulfonyl]-1,1-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 377 5-[(1,1-dimethyl-1,2,3,4- 427 TFA 5-iodo-3- tetrahydro[1]benzofuro[2,3- (trifluoromethyl)pyridin- c]pyridin-7-yl)sulfonyl]-3- 2(1H)-one (trifluoromethyl)pyridin-2(1H)- one 378 1,1-dimethyl-7-{[2- 411 HCl 3-iodo-2- (trifluoromethyl)pyridin-3- (trifluoromethyl)pyridine yl]sulfonyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 379 1,1-dimethyl-7-[(4- 357 TFA 3-iodo-4-methylpyridine methylpyridin-3-yl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 380 1,1-dimethyl-7-{[6-(pyrrolidin-1- 412 TFA 5-iodo-2-(pyrrolidin-1- yl)pyridin-3-yl]sulfonyl}-1,2,3,4- yl)pyridine tetrahydro[1]benzofuro[2,3- c]pyridine 381 7-[(5-fluoropyridin-3-yl)sulfonyl]- 361 HCl 3-fluoro-5-iodopyridine 1,1-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 382 7-[(2-fluoropyridin-3-yl)sulfonyl]- 335 racemic HCl 2-fluoro-3-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 383 7-[(2-fluoropyridin-3-yl)sulfinyl]- 319 racemic HCl 2-fluoro-3-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 384 7-[(2,3-difluorophenyl)sulfinyl]- 336 racemic HCl 1,2-difluoro-3- 1,2,3,4,4a,9a- iodobenzene hexahydro[1]benzofuro[2,3- c]pyridine 385 7-[(2,3,5- 354 racemic HCl 1,2,5-trifluoro-3- trifluorophenyl)sulfinyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 386 7-[(2,3,5- 370 racemic HCl 1,2,5-trifluoro-3- trifluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 387 methyl 3-chloro-5- 408 racemic HCl methyl 3-chloro-5- [1,2,3,4,4a,9a- iodobenzoate hexahydro[1]benzofuro[2,3- c]pyridin-7-ylsulfonyl]benzoate 388 7-[(2,3-difluorophenyl)sulfonyl]- 352 racemic HCl 2,3-difluorobenzenethiol 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 389 7-[(2-chloropyridin-3-yl)sulfinyl]- 335 diastereoisomers HCl 2-chloro-3-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 390 7-[(2-chloropyridin-3- 351 racemic HCl 2-chloro-3-iodopyridine yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 391 7-[(5-chloropyridin-3-yl)sulfinyl]- 335 diastereoisomers HCl 3-chloro-5-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 392 7-[(5-chloropyridin-3- 351 racemic HCl 3-chloro-5-iodopyridine yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 393 7-(pyridin-3-ylsulfonyl)- 317 racemic HCl 3-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 394 7-{[2-(2,2,2- 415 diastereoisomers HCl 3-iodo-2-(2,2,2- trifluoroethoxy)pyridin-3- trifluoroethoxy)pyridine yl]sulfonyl}-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 395 7-{[2-(2,2,2- 415 racemic HCl 3-iodo-2-(2,2,2- trifluoroethoxy)pyridin-3- trifluoroethoxy)pyridine yl]sulfonyl}-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 396 7-[(5-fluoropyridin-3-yl)sulfinyl]- 319 racemic HCl 3-fluoro-5-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 397 7-[(5-fluoropyridin-3-yl)sulfonyl]- 335 racemic HCl 3-fluoro-5-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 398 7-[(2-fluoropyridin-3-yl)sulfonyl]- 335 racemic HCl 2-fluoro-3-iodopyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 399 7-[(2,3-difluorophenyl)sulfonyl]- 352 Enantiomer 1 HCl 1,2-difluoro-3- 1,2,3,4,4a,9a- iodobenzene hexahydro[1]benzofuro[2,3- c]pyridine 400 7-[(2,3,5- 370 Enantiomer 1 HCl 1,2,5-trifluoro-3- trifluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 401 7-[(3-ethoxy-5- 378 Enantiomer 1 HCl 1-ethoxy-3-fluoro-5- fluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 402 7-{[3-fluoro-5-(2- 406 Enantiomer 1 HCl 1-fluoro-3-iodo-5-(2- methylpropoxy)phenyl]sulfonyl}- methylpropoxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 403 7-{[3-fluoro-5-(2,2,2- 432 Enantiomer 1 HCl 1-fluoro-3-iodo-5-(2,2,2- trifluoroethoxy)phenyl]sulfonyl}- trifluoroethoxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 404 7-[(2-fluoro-3- 364 Enantiomer 1 HCl 2-fluoro-1-iodo-3- methoxyphenyl)sulfonyl]- methoxybenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 405 7-(2,3-dihydro-1-benzofuran-4- 358 Enantiomer 1 HCl 4-iodo-2,3-dihydro-1- ylsulfonyl)-1,2,3,4,4a,9a- benzofuran hexahydro[1]benzofuro[2,3- c]pyridine 406 7-{[2-(propan-2- 374 Enantiomer 1 HCl 1-iodo-2-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 407 7-[(3-fluoro-5- 364 Enantiomer 1 HCl 1-fluoro-3-iodo-5- methoxyphenyl)sulfonyl]- methoxybenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 408 7-{[2-(2,2,2- 414 Enantiomer 1 HCl 1-iodo-2-(2,2,2- trifluoroethoxy)phenyl]sulfonyl}- trifluoroethoxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 409 7-[(3-chloro-2- 368 Enantiomer 1 HCl 1-chloro-2-fluoro-3- fluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 410 7-{[2-(trifluoromethyl)pyridin-3- 385 Enantiomer 1 HCl 3-iodo-2- yl]sulfonyl}-1,2,3,4,4a,9a- (trifluoromethyl)pyridine hexahydro[1]benzofuro[2,3- c]pyridine 411 7-[(2,3-difluorophenyl)sulfonyl]- 352 Enantiomer 2 HCl 1,2-difluoro-3- 1,2,3,4,4a,9a- iodobenzene hexahydro[1]benzofuro[2,3- c]pyridine 412 7-[(2,3,5- 370 Enantiomer 2 HCl 1,2,5-trifluoro-3- trifluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 413 7-[(3-ethoxy-5- 378 Enantiomer 2 HCl 1-ethoxy-3-fluoro-5- fluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 414 7-{[3-fluoro-5-(2- 406 Enantiomer 2 HCl 1-fluoro-3-iodo-5-(2- methylpropoxy)phenyl]sulfonyl}- methylpropoxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 415 7-{[3-fluoro-5-(2,2,2- 432 Enantiomer 2 HCl 1-fluoro-3-iodo-5-(2,2,2- trifluoroethoxy)phenyl]sulfonyl}- trifluoroethoxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 416 7-[(2-fluoro-3- 364 Enantiomer 2 HCl 2-fluoro-1-iodo-3- methoxyphenyl)sulfonyl]- methoxybenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 417 7-{[3-fluoro-5-(propan-2- 392 Enantiomer 2 HCl 1-fluoro-3-iodo-5- yloxy)phenyl]sulfonyl}- (propan-2-yloxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 418 7-(2,3-dihydro-1-benzofuran-4- 358 Enantiomer 2 HCl 4-iodo-2,3-dihydro-1- ylsulfonyl)-1,2,3,4,4a,9a- benzofuran hexahydro[1]benzofuro[2,3- c]pyridine 419 7-{[2-(propan-2- 374 Enantiomer 2 HCl 1-iodo-2-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 420 7-[(3-fluoro-5- 364 Enantiomer 2 HCl 1-fluoro-3-iodo-5- methoxyphenyl)sulfonyl]- methoxybenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 421 7-{[2-(2,2,2- 414 Enantiomer 2 HCl 1-iodo-2-(2,2,2- trifluoroethoxy)phenyl]sulfonyl}- trifluoroethoxy)benzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 422 7-[(3-chloro-2- 368 Enantiomer 2 HCl 1-chloro-2-fluoro-3- fluorophenyl)sulfonyl]- iodobenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 423 7-{[2-(trifluoromethyl)pyridin-3- 385 Enantiomer 2 HCl 3-iodo-2- yl]sulfonyl}-1,2,3,4,4a,9a- (trifluoromethyl)pyridine hexahydro[1]benzofuro[2,3- c]pyridine 424 7-{[3-fluoro-5-(2- 420 racemic HCl 1-fluoro-3-iodo-5-(2- methylpropoxy)phenyl]sulfonyl}- methylpropoxy)benzene 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 425 N,N-dimethyl-3-{[4a-methyl- 401 racemic HCl 3-iodo-N,N- 1,2,3,4,4a,9a- dimethylbenzamide hexahydro[1]benzofuro[2,3- c]pyridin-7- yl]sulfonyl}benzamide 426 7-[(3-ethoxy-5- 392 racemic HCl 1-ethoxy-3-fluoro-5- fluorophenyl)sulfonyl]-4a- iodobenzene methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 427 7-{[3-fluoro-5-(propan-2- 406 racemic HCl 1-fluoro-3-iodo-5- yloxy)phenyl]sulfonyl}-4a- (propan-2-yloxy)benzene methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 428 4-{[4a-methyl-1,2,3,4,4a,9a- 347 racemic HCl 4-iodopyridin-2(1H)-one hexahydro[1]benzofuro[2,3- c]pyridin-7-yl]sulfonyl}pyridin- 2(1H)-one 429 7-[(5-fluoropyridin-3-yl)sulfonyl]- 349 racemic HCl 3-fluoro-5-iodopyridine 4a-methyl-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 430 7-[(5-chloropyridin-3- 365 racemic HCl 3-chloro-5-iodopyridine yl)sulfonyl]-4a-methyl- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 431 4a-methyl-7-{[5- 399 racemic HCl 3-(trifluoromethyl)-5- (trifluoromethyl)pyridin-3- [(tripropan-2- yl]sulfonyl}-1,2,3,4,4a,9a- ylsilyl)sulfanyl]pyridine hexahydro[1]benzofuro[2,3- c]pyridine 432 7-[(2,3-difluorophenyl)sulfonyl]- 350 HCl 1,2-difluoro-3- 1,2,3,4- iodobenzene tetrahydro[1]benzofuro[2,3- c]pyridine 433 7-[(2-fluoropyridin-3-yl)sulfinyl]-4- 317 Racemic HCl 2-fluoro-3-iodopyridine 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 434 7-[(2-fluoropyridin-3-yl)sulfonyl]- 333 HCl 2-fluoro-3-iodopyridine 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 435 7-[(2-chloropyridin-3-yl)sulfinyl]- 333 Racemic HCl 2-chloro-3-iodopyridine 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 436 7-[(2-chloropyridin-3- 349 HCl 2-chloro-3-iodopyridine yl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 437 7-[(5-chloropyridin-3- 349 HCl 3-chloro-5-iodopyridine yl)sulfonyl]-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 438 7-(pyridin-3-ylsulfonyl)-1,2,3,4- 315 HCl 3-iodopyridine tetrahydro[1]benzofuro[2,3- c]pyridine 439 7-{[2-(propan-2-yloxy)pyridin-3- 373 HCl 3-iodo-2-(propan-2- yl]sulfonyl}-1,2,3,4- yloxy)pyridine tetrahydro[1]benzofuro[2,3- c]pyridine 440 7-{[2-(2,2,2- 413 HCl 3-iodo-2-(2,2,2- trifluoroethoxy)pyridin-3- trifluoroethoxy)pyridine yl]sulfonyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 441 7-[(5-fluoropyridin-3-yl)sulfonyl]- 333 HCl 3-fluoro-5-iodopyridine 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 442 6-[(2,3-difluorophenyl)sulfinyl]- 334 Racemic TFA 1,2-difluoro-3- 1,2,3,4- iodobenzene tetrahydro[1]benzofuro[2,3- c]pyridine 443 6-[(2,3,5- 352 Racemic TFA 1,2,5-trifluoro-3- trifluorophenyl)sulfinyl]-1,2,3,4- iodobenzene tetrahydro[1]benzofuro[2,3- c]pyridine 444 6-[(2-fluoropyridin-3-yl)sulfinyl]- 317 Racemic TFA 2-fluoro-3-iodopyridine 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 445 6-[(2-chloropyridin-3-yl)sulfinyl]- 333 Racemic TFA 2-chloro-3-iodopyridine 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 446 6-{[2-(propan-2-yloxy)pyridin-3- 357 Racemic TFA 3-iodo-2-(propan-2- yl]sulfinyl}-1,2,3,4- yloxy)pyridine tetrahydro[1]benzofuro[2,3- c]pyridine 447 6-{[2-(2,2,2- 397 Racemic TFA 3-iodo-2-(2,2,2- trifluoroethoxy)pyridin-3- trifluoroethoxy)pyridine yl]sulfinyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 448 6-{[2-(2,2,2- 413 TFA 3-iodo-2-(2,2,2- trifluoroethoxy)pyridin-3- trifluoroethoxy)pyridine yl]sulfonyl}-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 449 6-{[2-(propan-2-yloxy)pyridin-3- 373 TFA 3-iodo-2-(propan-2- yl]sulfonyl}-1,2,3,4- yloxy)pyridine tetrahydro[1]benzofuro[2,3- c]pyridine 450 7-[(5-methoxy-1-oxidopyridin-3- 389 HCl 3-iodo-5-methoxypyridine yl)sulfonyl]-4,4-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 451 7-[(5-methoxypyridin-3- 373 HCl 3-iodo-5-methoxypyridine yl)sulfonyl]-4,4-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 452 7-[(5-chloropyridin-3- 377 HCl 3-chloro-5-iodopyridine yl)sulfonyl]-4,4-dimethyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 453 7-[(5-methoxy-1-oxidopyridin-3- 445 racemic HCl 3-iodo-5-methoxypyridine yl)sulfonyl]-4,4-dimethyl- 3,4,4′,5′-tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine-1,3′- furan] 454 7-[(5-methoxypyridin-3- 429 racemic HCl 3-iodo-5-methoxypyridine yl)sulfonyl]-4,4-dimethyl- 3,4,4′,5′-tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine-1,3′- furan] 455 7-[(5-chloropyridin-3-yl)sulfinyl]- 417 racemic HCl 3-chloro-5-iodopyridine 4,4-dimethyl-3,4,4′,5′- tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine-1,3′- furan] 456 7-[(5-chloropyridin-3- 433 racemic HCl 3-chloro-5-iodopyridine yl)sulfonyl]-4,4-dimethyl- 3,4,4′,5′-tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine-1,3′- furan] 457 7-(2,3-dihydro-1,4-benzodioxin- 374 enantiomer 1 HCl (2,3-dihydro-1,4- 5-ylsulfonyl)-1,2,3,4,4a,9a- benzodioxin-5- hexahydro[1]benzofuro[2,3- ylsulfanyl)(tripropan-2- c]pyridine yl)silane 458 7-[(3,5-difluoro-2- 382 enantiomer 1 HCl [(3,5-difluoro-2- methoxyphenyl)sulfonyl]- methoxyphenyl)sulfanyl](tripropan- 1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 459 7-{[5-(trifluoromethyl)pyridin-3- 385 enantiomer 1 HCl 3-(trifluoromethyl)-5- yl]sulfonyl}-1,2,3,4,4a,9a- [(tripropan-2- hexahydro[1]benzofuro[2,3- ylsilyl)sulfanyl]pyridine c]pyridine 460 7-[(2,2-difluoro-1,3-benzodioxol- 410 racemic HCl [(2,2-difluoro-1,3- 4-yl)sulfonyl]-4a-methyl- benzodioxol-4- 1,2,3,4,4a,9a- yl)sulfanyl](tripropan-2- hexahydro[1]benzofuro[2,3- yl)silane c]pyridine 461 7-[(2,2-difluoro-1,3-benzodioxol- 396 enantiomer 2 HCl [(2,2-difluoro-1,3- 4-yl)sulfonyl]-1,2,3,4,4a,9a- benzodioxol-4- hexahydro[1]benzofuro[2,3- yl)sulfanyl](tripropan-2- c]pyridine yl)silane 462 7-(2,3-dihydro-1,4-benzodioxin- 374 enantiomer 2 HCl (2,3-dihydro-1,4- 5-ylsulfonyl)-1,2,3,4,4a,9a- benzodioxin-5- hexahydro[1]benzofuro[2,3- ylsulfanyl)(tripropan-2- c]pyridine yl)silane 463 7-[(3,5-difluoro-2- 382 enantiomer 2 HCl [(3,5-difluoro-2- methoxyphenyl)sulfonyl]- methoxyphenyl)sulfanyl](tripropan- 1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 464 7-{[5-(trifluoromethyl)pyridin-3- 385 enantiomer 2 HCl 3-(trifluoromethyl)-5- yl]sulfonyl}-1,2,3,4,4a,9a- [(tripropan-2- hexahydro[1]benzofuro[2,3- ylsilyl)sulfanyl]pyridine c]pyridine 465 7-[(2,2-difluoro-1,3-benzodioxol- 422 TFA [(2,2-difluoro-1,3- 4-yl)sulfonyl]-1,1-dimethyl- benzodioxol-4- 1,2,3,4- yl)sulfanyl](tripropan-2- tetrahydro[1]benzofuro[2,3- yl)silane c]pyridine 466 7-(2,3-dihydro-1,4-benzodioxin- 400 HCl (2,3-dihydro-1,4- 5-ylsulfonyl)-1,1-dimethyl- benzodioxin-5- 1,2,3,4- ylsulfanyl)(tripropan-2- tetrahydro[1]benzofuro[2,3- yl)silane c]pyridine 467 7-(2,3-dihydro-1,4-benzodioxin- 372 HCl (2,3-dihydro-1,4- 5-ylsulfonyl)-1,2,3,4- benzodioxin-5- tetrahydro[1]benzofuro[2,3- ylsulfanyl)(tripropan-2- c]pyridine yl)silane 468 7-(2,3-dihydro-1,4-benzodioxin- 388 racemic HCl (2,3-dihydro-1,4- 5-ylsulfonyl)-4a-methyl- benzodioxin-5- 1,2,3,4,4a,9a- ylsulfanyl)(tripropan-2- hexahydro[1]benzofuro[2,3- yl)silane c]pyridine 469 7-[(2,2-difluoro-1,3-benzodioxol- 396 single HCl [(2,2-difluoro-1,3- 4-yl)sulfonyl]-1,2,3,4,4a,9a- enantiomer, benzodioxol-4- hexahydro[1]benzofuro[2,3- absolute yl)sulfanyl](tripropan-2- c]pyridine stereochemistry yl)silane unknown 470 7-[(3,5-difluoro-2- 408 HCl [(3,5-difluoro-2- methoxyphenyl)sulfonyl]-1,1- methoxyphenyl)sulfanyl](tripropan- dimethyl-1,2,3,4- 2-yl)silane tetrahydro[1]benzofuro[2,3- c]pyridine

Example 471 Enantiomer 1 1-(Difluoromethyl)-7-[(2,3-difluorophenyl)sulfonyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine, enantiomer 1

Step 1 1-(Difluoromethyl)-7-[(2,3-difluorophenyl)sulfanyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine

Into a Schlenk flask equipped with a magnetic stir bar was added 1-difluoromethyl-7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-C]pyridine (enantiomer 1, 100 mg, 0.30 mmol), (2,3-difluorophenylsulfanyl)-triisopropylsilane (125 mg, 0.43 mmol), CsF (189 mg, 1.24 mmol), CuI (25 mg, 0.13 mmol), ethylene glycol (85 μL, 1.5 mmol) and anhydrous DMF (3 mL, 0.30 mmol). The Schlenck flask was evacuated and flushed with argon three times. The reaction mixture was heated at 105° C. under argon for 17 h. Upon cooling, the reaction was diluted with DCM, filtered through celite and solvent was evaporated. Purification using preparative TLC (2000 micron silica gfel plate; elution with 15% EtOAc in dichloromethane) afforded 155 mg of product as a viscous, pale oil. MS m/z: 382 [M+H]⁺.

Step 2 1-(Difluoromethyl)-7-[(2,3-difluorophenyl)sulfonyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine, enantiomer 1

To a suspension of 1-difluoromethyl-7-(2,3-difluorophenylsulfanyl)-1-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine (155 mg, 0.53 mmol) in methanol (3 mL) and water (2 mL) stirring at rt was added Oxone® (0.390 g, 0.63 mmol). The reaction was stirred at rt for 36 h, then filtered through celite. The filtrate was extracted with dichloromethane, the organic phase was washed with water, sat. sodium bicarbonate and dried over sodium sulfate. Concentration and preparative TLC (2000 micron silica gel plate eluting with 12% EtOAc in dichloromethane) afforded 45 mg of the free base as a clear, viscous oil. The oil was dissolved in 4 M HCl in 1,4-dioxanes (1 mL) and triturated with anhydrous diethyl ether. The precipitate was collected by filtration, dried under high vacuum at 90° C. for 16 h to afford 36 mg of product as an off-white solid, mp 247-250° C. MS m/z: 414 [M+H]⁺. ¹HNMR (DMSO) δ 8.28 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.95 (m, 2H), 7.88 (m, 1H), 6.62 (t, J=55 Hz, 1H), 3.75 (br.s, 2H), 3.57 (m, 2H), 2.98 (m, 2H), 1.72 (s, 3H).

Example 472 Enantiomer 2 1-(Difluoromethyl)-7-[(2,3-difluorophenyl)sulfonyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine, enantiomer 2

Prepared as described for example 471 starting from enantiomer 2 of 1-difluoromethyl-7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridine and (2,3-difluorophenylsulfanyl)-triisopropylsilane. mp 249-252° C.; MS m/z: 414 [M+H]⁺.

Example 473 Enantiomer 2 7-[(2,3-Difluorophenyl)sulfonyl]-3,4,4′,5-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan], enantiomer 1

Prepared as described for example 471 starting from enantiomer 1 of 7-iodo-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan] and (2,3-difluorophenylsulfanyl)-triisopropylsilane. mp 269-272° C.; MS m/z: 406 [M+H]⁺.

Example 474 N,N-Dimethyl-3-(1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-7-ylsulfonyl)benzamide hydrochloride

Into a Schlenk apparatus was added 7-triisopropylsilanylsulfanyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (140 mg, 0.303 mmol), 3-iodo-N,N-dimethylbenzamide (170 mg, 0.61 mmol), copper (I) iodide (30 mg, 0.20 mmol), cesium fluoride (92 mg, 0.61 mmole), 1,2-ethanediol (0.07 mL, 1.0 mmol), and anhydrous DMF (1 mL, 10 mmol). The suspension was evacuated three times under high vacuum flushing with argon each time. After heating at 105° C. for 18 h, the reaction mixture was cooled, diluted with DCM, filtered through celite and the filtrate concentrated. Purification using preparative thin layer chromatography (2000 micron silica gel plate; 5% MeOH in dichloromethane) afforded N,N-dimethyl-3-(1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-7-ylsulfonyl)benzamide, which was dissolved in DCM (2 mL). mCPBA (50%) was added, the reaction mixture was stirred for 18 h, diluted with DCM, and washed with sat. sodium bicarbonate. The organic phase was dried over sodium sulfate, concentrated and the resulting oil was purified by preparative TLC (2000 micron silica gel plate; 5% MeOH containing 2% isopropanol in dichloromethane) to afforded 34 mg of N,N-dimethyl-3-(1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-7-ylsulfonyl)benzamide. The solid was converted to the HCl salt by adding 4M HCl in 1,4-dioxane (2 mL, 8.0 mmol) which was collected by filtration and dried under vacuum at 90° C. overnight to afford 18.8 mg of N,N-dimethyl-3-(1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-7-ylsulfonyl)benzamide hydrochloride as a light tan solid, mp 262-265° C. MS m/z: 385 [M+H]⁺. ¹HNMR (DMSO) δ 9.78 (br.s, 2H), 8.36 (d, J=1.2 Hz, 1H), 8.06 (m, 1H), 7.99 (s, 1H), 7.92 (m, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.69 (m, 2H), 4.47 (s, 2H), 3.44 (m, 2H), 2.99 (s, 3H), 2.95 (m, 2H), 2.84 (s, 3H).

The following examples were prepared essentially as described above. Example 489 and Example 490 in the Table below were isolated from racemic mixture Example 487 using SFC chromatography on a chiral column as described in the general method.

Ex. MS m/z # Name Mp (° C.) [M + H]⁺ Stereochemistry Salt Starting material 474 N,N-dimethyl-3-(1,2,3,4- 262-265 385 HCl 3-iodo-N,N- tetrahydro[1]benzofuro[2,3- dimethylbenzamide c]pyridin-7- ylsulfonyl)benzamide 475 7-[(2,3- 250-265 420 HCl [(2,3- difluorophenyl)sulfonyl]- difluorophenyl)sulfanyl](tripropan- 2′,3,3′,4,5′,6′-hexahydro- 2-yl)silane 2H-spiro[1- benzofuro[2,3-c]pyridine- 1,4′-pyran] 476 2-fluoro-6-(1,2,3,4,4a,9a- 283-286 405 Racemic HCl 2-fluoro-6-iodo-N,N- hexahydro[1]benzofuro[2,3- dimethylbenzamide c]pyridin-7-ylsulfonyl)- N,N-dimethylbenzamide 477 2-fluoro-6-(1,2,3,4,4a,9a- >200 391 Racemic HCl 2-fluoro-6-iodo-N,N- hexahydro[1]benzofuro[2,3- dimethylbenzamide c]pyridin-7-ylsulfonyl)- N-methylbenzamide 478 N-methyl-3-(1,2,3,4- >290 371 HCl 3-iodo-N-methylbenzamide tetrahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl)benzamide 479 2-fluoro-N,N-dimethyl-6- 245-248 403 HCl 2-fluoro-6-iodo-N,N- (1,2,3,4- dimethylbenzamide tetrahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl)benzamide 480 7-[(3,5- 248-251 376 racemic HCl [(3,5- dimethoxyphenyl)sulfonyl]- dimethoxyphenyl)sulfanyl](tripropan- 1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 481 7-{[2-fluoro-3-(propan-2- 221-223 392 Enantiomer 1 HCl {[2-fluoro-3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)phenyl]sulfanyl}(tripropan-2- 1,2,3,4,4a,9a- yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 482 7-{[2-fluoro-3-(tetrahydro- 175-177 448 Enantiomer 2 HCl {[(2E,4Z)-4-fluoro-5-(tetrahydro- 2H-pyran-4- 2H-pyran-4-ylmethoxy)hepta- ylmethoxy)phenyl]sulfonyl}- 2,4,6-trien-3-yl]sulfanyl}(tripropan- 1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 483 7-{[2-fluoro-3-(propan-2- 221-224 392 Enantiomer 2 HCl {[2-fluoro-3-(propan-2- yloxy)phenyl]sulfonyl}- yloxy)phenyl]sulfanyl}(tripropan-2- 1,2,3,4,4a,9a- yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 484 7-{[3-(benzyloxy)-5- 171-172 440 Enantiomer 2 HCl {[3-(benzyloxy)-5- fluorophenyl]sulfonyl}- fluorophenyl]sulfanyl}(tripropan-2- 1,2,3,4,4a,9a- yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 485 7-{[2-chloro-3- 185-187 464 Enantiomer 2 HCl {[(2E,4Z)-4-chloro-5-(tetrahydro- (tetrahydro-2H-pyran-4- 2H-pyran-4-ylmethoxy)hepta- ylmethoxy)phenyl]sulfonyl}- 2,4,6-trien-3-yl]sulfanyl}(tripropan- 1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 486 7-[(3,5-difluoro-2- 259-261 396 racemic HCl [(3,5-difluoro-2- methoxyphenyl)sulfonyl]- methoxyphenyl)sulfanyl](tripropan- 4a-methyl-1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 487 7-[(3,5- 283-285 390 racemic HCl [(3,5- dimethoxyphenyl)sulfonyl]- dimethoxyphenyl)sulfanyl](tripropan- 4a-methyl- 2-yl)silane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 488 7-[(2,3- 202-204 366 racemic HCl [(2,3- difluorophenyl)sulfonyl]- difluorophenyl)sulfanyl](tripropan- 4a-methyl-1,2,3,4,4a,9a- 2-yl)silane hexahydro[1]benzofuro[2,3- c]pyridine 489 7-[(3,5- 254-255 390 Enantiomer1 HCl [(3,5- dimethoxyphenyl)sulfonyl]- dimethoxyphenyl)sulfanyl](tripropan- 4a-methyl- 2-yl)silane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 490 7-[(3,5- 250-252 390 Enantiomer2 HCl [(3,5- dimethoxyphenyl)sulfonyl]- dimethoxyphenyl)sulfanyl](tripropan- 4a-methyl- 2-yl)silane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 491 N-[7-(3-Fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]-isobutyramide

Step 1 2-(7-Iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isoindole-1,3-dione

To a mixture of 2-(6-iodo-benzofuran-3-yl)-ethylamine (2.00 g, 6.97 mmol) and 2-(2-oxo-propyl)-isoindole-1,3-dione (4.25 g, 20.9 mmol) was added trifluoroacetic acid (8.00 mL, 104 mmol) and then heated at 80° C. After 16 h, additional ketone (3 eq) was added and heating continued. After a total of 3 days, the reaction mixture was basified (DCM-aq. NaHCO₃) and the resulting precipitate was filtered, rinsed with DCM and dried to give an off-white solid. mp 302-304° C. dec.; MS m/z 473 [M+H]⁺.

Step 2 N-[7-(3-Fluoro-phenylsulfanyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]-isobutyramide

A suspension of 2-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isoindole-1,3-dione (0.472 g, 1.00 mmol) in ethanol (10.00 mL, 171.3 mmol) was refluxed with hydrazine monohydrate (200 mg, 4 mmol). After 4 h, cooled, filtered, rinsed with MeOH, the filtrate concentrated and dried under vacuum. The resulting deprotected amine was dissolved in pyridine (5.00 mL, 61.8 mmol) and propanoic acid-2-methyl-anhydride (0.332 mL, 2.00 mmol) was added. After 1 h at room temperature, water was added (30 mL) and the mixture was stirred overnight. DCM was added and the organic layer was washed with NaHCO₃ and evaporated. The crude product was purified using silica gel chromatography using DCM/MeOH/NH₄OH to afford (7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isobutyramide. MS m/z 413 [M+H]⁺, which was taken directly into the next step.

To N-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isobutyramide (230 mg, 0.56 mmol), neocuproine (11.6 mg, 0.0558 mmol) and copper (I) iodide (53.1 mg, 0.279 mmol) was added dry N,N-dimethylformamide (4 mL, 50 mmol). 3-Fluorobenzenethiol (104 μL, 1.23 mmol) was added neat followed immediately by the addition of the sodium tert-butoxide (118 mg, 1.23 mmol). The reaction mixture was stirred at 100° C. After 48 h, the reaction mixture was cooled to room temperature and concentrated. The residual solid was partially dissolved into a 5% MeOH in DCE solution and flushed through a plug of Celite. The concentrated filtrate was chromatographed with DCM-MeOH—NH₄OH to afford a brownish yellow gum. MS m/z 413 [M+H]⁺.

Step 3 N-[7-(3-Fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]-isobutyramide

To a solution of N-[7-(3-fluoro-phenylsulfanyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isobutyramide (0.200 g, 0.485 mmol) in methanol (10.0 mL, 247 mmol) was added a solution of Oxone® (0.745 g, 1.21 mmol) in water (5.0 mL, 280 mmol) and the reaction was stirred at room temperature overnight. After 6 h, the mixture was filtered, concentrated, and then extracted with DCM/sat. aq. NaHCO₃. The organic phase was dried, concentrated and then purified by silica gel chromatography with DCM-MeOH—NH₄OH to obtain the free base. The HCl salt was made (EtOH—HCl) to provide an off-white solid. mp 220-225° C. dec.; MS m/z 445 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.1 (dd, J=7 Hz, 6H), 1.45 (s, 3H), 2.3 (m, 1H), 2.66 (m, 2H), 3.15 (m, 2H), 3.5 (m, 1H), 3.67 (m, 1H), 5.9 (brs, 1H), 7.25 (m, 1H), 7.5 (m, 1H), 7.56 (m, 1H), 7.66 (m, 1H), 7.77 (m, 1H), 7.83 (m, 1H), 8.07 (s, 1H).

Example 492 N-({7-[(3-fluorophenyl)sulfonyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide

Prepared as described for N-[7-(3-Fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isobutyramide using acetic anhhydride instead of 2-methylpropanoic anhydride. mp 140-155° C. dec.; MS m/z 417 [M+H]⁺.

Example 493 1-{7-[(3-Fluorophenyl)sulfonyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methanamine

Step 1 2-({7-[(3-Fluorophenyl)sulfanyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)-1H-isoindole-1,3(2H)-dione

To 2-(7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl)-isoindole-1,3-dione (0.192 g, 0.406 mmol) was added sodium tert-butoxide (117 mg, 1.22 mmol), copper (I) iodide (7.74 mg, 0.0406 mmol), 1,2-ethanediol (45.3 μL, 0.812 mmol), N,N-dimethylformamide (4.00 mL, 51.6 mmol), and finally 3-fluorobenzenethiol (36.0 μL, 0.427 mmol). The reaction mixture was flushed with N₂ and heated at 120° C. under a N₂ atmosphere. After 72 h, the reaction was cooled to room temperature and concentrated. The residual solid was partially dissolved into a 5% MeOH in DCM solution and flushed through a plug of Celite. The concentrated filtrate was chromatographed on silica gel using DCM-MeOH—NH₄OH to afford a brownish yellow gum. MS m/z 473 [M+H]⁺.

Step 2 1-{7-[(3-Fluorophenyl)sulfonyl]-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methanamine

To a solution of 2-[7-(3-fluoro-phenylsulfanyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isoindole-1,3-dione (0.150 g, 0.317 mmol) in methanol (10.0 mL, 247 mmol) was added a solution of Oxone® (0.488 g, 0.794 mmol) in water (5.0 mL, 280 mmol) and the reaction mixture was stirred at room temperature overnight. After 3 h, the reaction was filtered, concentrated, and extracted with DCM/sat. aq. NaHCO₃. The organic layer was dried, concentrated and purified by chromatography to afford 2-[7-(3-fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isoindole-1,3-dione as an off-white solid. A suspension of 2-[7-(3-fluoro-benzenesulfonyl)-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-c]pyridin-1-ylmethyl]isoindole-1,3-dione (0.015 g, 0.030 mmol) in ethanol (5.00 mL, 85.6 mmol) was refluxed with hydrazine monohydrate (0.040 mL, 0.80 mmol). After 4 h, the reaction was cooled, filtered, rinsed with MeOH, and the filtrate concentrated and dried under vacuum to afford a yellowish white solid. mp>250° C. dec.; MS m/z 375 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.5 (s, 3H), 2.7 (m, 2H), 3.15 (m, 1H), 3.36 (m, 1H), 4.0 (d, J=14 Hz, 1H), 4.15 (d, J=14 Hz, 1H), 7.2-8.0 (m, 7H)

Example 494 1-Butyl-6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine

Pentanal (12 μL, 1.5 eq) was added to a solution of {2-[6-(3-fluoro-benzenesulfonyl)-benzofuran-3-yl]-ethyl}-carbamic acid tert-butyl ester (800 μL, 0.125 M) in DCE:TFA 1:1. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. MS m/z 388 [M+H]⁺.

The following examples were prepared essentially as described above. Example 530 was isolated from the corresponding racemic mixture (Example 508) using SFC chromatography on a chiral column as described in the general method.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 494 1-butyl-6-[(3- 388 Racemic TFA pentanal fluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 495 7-[(3-fluorophenyl)sulfonyl]- 374 Racemic HCl 2-methylpropanal 1-(propan-2-yl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 496 7-[(3-fluorophenyl)sulfonyl]- 416 Racemic TFA tetrahydro-2H-pyran-4- 1-(tetrahydro-2H-pyran-4- carbaldehyde yl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 497 1-(2-bromoethyl)-7-[(3- 438 Racemic TFA 3-bromo-1,1- fluorophenyl)sulfonyl]- dimethoxypropane 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 498 7-[(3-fluorophenyl)sulfonyl]- 376 Racemic TFA 1,1,2-trimethoxyethane 1-(methoxymethyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 499 1-butyl-7-[(3- 404 Racemic TFA pentanal chlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 500 7-[(3- 432 Racemic TFA tetrahydro-2H-pyran-4- chlorophenyl)sulfonyl]-1- carbaldehyde (tetrahydro-2H-pyran-4-yl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 501 1-(2-bromoethyl)-7-[(3- 453 Racemic TFA 3-bromo-1,1- chlorophenyl)sulfonyl]- dimethoxypropane 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 502 7-[(3- 392 Racemic TFA 1,1,2-trimethoxyethane chlorophenyl)sulfonyl]-1- (methoxymethyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 503 7-[(3- 388 Racemic TFA cyclopropanecarbaldehyde chlorophenyl)sulfonyl]-1- cyclopropyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 504 7-[(3- 430 Racemic TFA 3,3,3-trifluoropropanal chlorophenyl)sulfonyl]-1- (2,2,2-trifluoroethyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 505 7-[(3- 390 Racemic TFA 2-methylpropanal chlorophenyl)sulfonyl]-1- (propan-2-yl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 506 1-butyl-7-[(3- 388 Racemic TFA pentanal fluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 507 7-[(3-fluorophenyl)sulfonyl]- 414 Racemic TFA 3,3,3-trifluoropropanal 1-(2,2,2-trifluoroethyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 508 1-(difluoromethyl)-7-[(3- 396 racemic 0 1,1-difluoropropan-2-one fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 509 1-(difluoromethyl)-7-[(3- 382 racemic HCl 1-ethoxy-2,2- fluorophenyl)sulfonyl]- difluoroethanol 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 510 7-[(3-fluorophenyl)sulfonyl]- 400 Racemic HCl trifluoroacetaldehyde 1-(trifluoromethyl)-1,2,3,4- hydrate tetrahydro[1]benzofuro[2,3- c]pyridine 511 6-[(3-fluorophenyl)sulfonyl]- 400 racemic HCl trifluoroacetaldehyde 1-(trifluoromethyl)-1,2,3,4- hydrate tetrahydro[1]benzofuro[2,3- c]pyridine 512 6-[(3-fluorophenyl)sulfonyl]- 374 Racemic HCl 2-methylpropanal 1-(propan-2-yl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 513 1-cyclopentyl-6-[(3- 400 diastereoisomers TFA cyclopentanecarbaldehyde fluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 514 1-(2-bromoethyl)-6-[(3- 438 Racemic TFA 3-bromo-1,1- fluorophenyl)sulfonyl]- dimethoxypropane 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 515 6-[(3-fluorophenyl)sulfonyl]- 376 Racemic TFA 1,1,2-trimethoxyethane 1-(methoxymethyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 516 6-[(3-fluorophenyl)sulfonyl]- 402 diastereoisomers TFA tetrahydrofuran-3- 1-(tetrahydrofuran-3-yl)- carbaldehyde 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 517 1-cyclopropyl-6-[(3- 372 Racemic TFA cyclopropanecarbaldehyde fluorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 518 6-[(3-fluorophenyl)sulfonyl]- 414 Racemic TFA 3,3,3-trifluoropropanal 1-(2,2,2-trifluoroethyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 519 6-[(3-fluorophenyl)sulfonyl]- 428 Racemic TFA 4,4,4-trifluorobutanal 1-(3,3,3-trifluoropropyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 520 6-[(3-fluorophenyl)sulfonyl]- 416 Racemic TFA tetrahydro-2H-pyran-4- 1-(tetrahydro-2H-pyran-4- carbaldehyde yl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 521 7-[(3- 418 diastereoisomers TFA tetrahydrofuran-3- chlorophenyl)sulfonyl]-1- carbaldehyde (tetrahydrofuran-3-yl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 522 7-[(3- 444 Racemic TFA 4,4,4-trifluorobutanal chlorophenyl)sulfonyl]-1- (3,3,3-trifluoropropyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 523 1-(difluoromethyl)-7- 364 racemic 1-ethoxy-2,2- (phenylsulfonyl)-1,2,3,4- difluoroethanol tetrahydro[1]benzofuro[2,3- c]pyridine 524 1-(difluoromethyl)-1- 378 racemic HCl 1,1-difluoropropan-2-one methyl-7-(phenylsulfonyl)- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 525 [1-methyl-7- 358 racemic HCl 1-hydroxypropan-2-one (phenylsulfonyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridin-1-yl]methanol 526 1-(difluoromethyl)-7-[(3- 394.1 racemic HCl 1,1-difluoropropan-2-one fluorophenyl)sulfonyl]-1- methyl-2,3,4,9-tetrahydro- 1H-beta-carboline 527 7-[(3-fluorophenyl)sulfonyl]- 398.1 racemic HCl trifluoroacetaldehyde 1-(trifluoromethyl)-2,3,4,9- hydrate tetrahydro-1H-beta- carboline 528 7-[(3-fluorophenyl)sulfonyl]- 412.1 racemic HCl 1,1,1-trifluoropropan-2-one 1-methyl-1- (trifluoromethyl)-2,3,4,9- tetrahydro-1H-beta- carboline 529 1-(difluoromethyl)-7-[(3- 380.1 racemic HCl 1-ethoxy-2,2- fluorophenyl)sulfonyl]- difluoroethanol 2,3,4,9-tetrahydro-1H-beta- carboline 530 1-(difluoromethyl)-7-[(3- 396 enantiomer 1 HCl 1,1-difluoropropan-2-one fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine

Example 531 N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide

2,2-Dimethoxyethylamine (16 μL, 1.5 eq) was dissolved in DCE (400 μL), acetic anhydride (15 μL, 1.5 eq) was added and the solution was shaken for 10 min. The resulting solution of N-(2,2-dimethoxyethyl)acetamide in DCE was added to a solution of tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate (800 μL, 0.125 M) in DCE:TFA 1:1. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. MS m/z 403 [M+H]⁺.

Example 532 N-(2-{6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}ethyl)acetamide

Prepared as described for N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide using tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate and N-[1,3]dioxolan-2-yl-ethylamine)-acetamide, which was prepared from 2-[1,3]dioxolan-2-yl-ethylamine and acetic anhydride. MS m/z 417 [M+H]⁺.

Example 533 N-({6-[(3-Fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)-N-methylacetamide

Prepared as described for N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide using tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate and N-[1,3]dioxolan-2-ylmethyl-methyl)-acetamide, which was prepared from [1,3]dioxolan-2-ylmethyl-methyl-amine and acetic anhydride. MS m/z 417 [M+H]⁺.

Example 534 N-(2-{6-[(3-Fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}ethyl)-N-methylacetamide

Prepared as described for N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide using tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate and N-(2-[1,3]dioxolan-2-yl-ethyl)-methyl-acetamide, which was prepared from (2-[1,3]dioxolan-2-yl-ethyl)-methyl-amine and acetic anhydride. MS m/z 431 [M+H]⁺.

The following examples were prepared essentially as described in the above synthetic procedures.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 535 N-({7-[(3-fluorophenyl)sulfonyl]-1,2,3,4- 403 Racemic TFA N-(2,2-dimethoxy- tetrahydro[1]benzofuro[2,3-c]pyridin-1- ethyl)-acetamide yl}methyl)acetamide 536 N-(2-{7-[(3-fluorophenyl)sulfonyl]- 417 Racemic TFA N-(2-[1,3]Dioxolan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-yl-ethylamine)- c]pyridin-1-yl}ethyl)acetamide acetamide 537 N-({7-[(3-fluorophenyl)sulfonyl]-1,2,3,4- 417 Racemic TFA N-[1,3]dioxolan-2- tetrahydro[1]benzofuro[2,3-c]pyridin-1- ylmethyl-methyl)- yl}methyl)-N-methylacetamide acetamide 538 N-(2-{7-[(3-fluorophenyl)sulfonyl]- 431 racemic HCl N-(2-[1,3]dioxolan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-yl-ethyl)-methyl- c]pyridin-1-yl}ethyl)-N-methylacetamide acetamide 539 N-({7-[(3-chlorophenyl)sulfonyl]-1,2,3,4- 419 Racemic TFA N-(2,2-dimethoxy- tetrahydro[1]benzofuro[2,3-c]pyridin-1- ethyl)-acetamide yl}methyl)acetamide 540 N-(2-{7-[(3-chlorophenyl)sulfonyl]- 433 Racemic TFA N-(2-[1,3]Dioxolan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-yl-ethylamine)- c]pyridin-1-yl}ethyl)acetamide acetamide 541 N-({7-[(3-chlorophenyl)sulfonyl]-1,2,3,4- 433 Racemic TFA N-[1,3]dioxolan-2- tetrahydro[1]benzofuro[2,3-c]pyridin-1- ylmethyl-methyl)- yl}methyl)-N-methylacetamide acetamide 542 N-(2-{7-[(3-chlorophenyl)sulfonyl]- 447 Racemic TFA N-(2-[1,3]dioxolan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-yl-ethyl)-methyl- c]pyridin-1-yl}ethyl)-N-methylacetamide acetamide

Example 543 7-(Phenylsulfonyl)-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]hydrochloride Enantiomer 1

Copper (I) iodide (0.144 g, 0.758 mmol) was added to a stirring solution of N,N-dimethyl-1,2-ethanediamine (0.166 mL, 1.52 mmol) in DMSO (8 mL, 70 mmol). The reaction was stirred at RT for 10 minutes to yield a dark green solution. N,N-diisopropylethylamine (0.991 mL, 5.69 mmol), sodium benzenesulfinate (1.87 g, 11.4 mmol) and 7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran] (enantiomer 1, 1.4 g, 3.8 mmol) were added sequentially. The reaction was flushed with argon and stirred at 100° C. for 18 h. After cooling to r.t., the reaction mixture was poured into water (24 mL), the solids were filtered and washed with water. The combined solids were dissolved in DCM, washed with water (2×), saturated aqueous ammonium chloride (3×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. This crude product was purified by preparative LC/MS. The resulting product was suspended in DCM and washed with 1N aqueous sodium hydroxide (3×) and water (3×). The free base was dissolved into a small amount of DCM and 1.0 N HCl in diethyl ether was added. Solvent evaporation afforded 1.06 g of 7-(phenylsulfonyl)-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]hydrochloride. MS m/z 384 [M+H]⁺.

Example 544 7-(Phenylsulfonyl)-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]hydrochloride (Enantiomer 2)

Prepared as described for 7-(phenylsulfonyl)-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]hydrochloride Enantiomer 1 using enantiomer 2 of 7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran] and sodium benzenesulfinate. MS m/z 384 [M+H]⁺.

Example 545 7-(Phenylsulfonyl)-2,2′,3,3′,4,5′,6′,9-octahydrospiro[beta-carboline-1,4′-pyran]trifluoroacetate

Prepared as described for 7-(phenylsulfonyl)-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]hydrochloride using 7-iodo-2,2′,3,3′,4,5′,6′,9-octahydrospiro[beta-carboline-1,4′-pyran] and sodium benzenesulfinate. After 18 h heating at 100° C., the reaction mixture was cooled to r.t., diluted with DMSO, filtered and purified by preparative LC/MS to afford 7-(phenylsulfonyl)-2,2′,3,3′,4,5′,6′,9-octahydrospiro[beta-carboline-1,4′-pyran]trifluoroacetic acid salt. MS m/z 383 [M+H]⁺.

Example 546 7-(Phenylsulfonyl)-2,3,4,4′,5′,9-hexahydrospiro[beta-carboline-1,3′-furan]trifluoroacetate

Prepared as described for 7-(phenylsulfonyl)-2,2′,3,3′,4,5′,6′,9-octahydrospiro[beta-carboline-1,4′-pyran] using 7-iodo-2,3,4,4′,5′,9-hexahydrospiro[beta-carboline-1,3′-furan] and sodium benzenesulfinate. MS m/z 369 [M+H]⁺.

Example 547 7-Iodo-2,3,4,5′,6′,9-hexahydro-4′H-spiro[beta-carboline-1,3′-pyran]trifluoroacetate

Prepared as described for 7-(phenylsulfonyl)-2,2′,3,3′,4,5′,6′,9-octahydrospiro[beta-carboline-1,4′-pyran] using 7-iodo-2,3,4,5′,6′,9-hexahydro-4′H-spiro[beta-carboline-1,3′-pyran] and sodium benzenesulfinate. MS m/z 369 [M+H]⁺.

Example 548 7-{[3-(Tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine

7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (enantiomer 2, 42 mg, 0.097 mmol) and 4-bromomethyl-tetrahydropyran (26 mg, 0.15 mmol) were dissolved in acetonitrile (1 ml). Cesium carbonate (95 mg, 0.29 mmol) was added, and the mixture was heated to 60° C. overnight. The solvent was evaporated and the residue purified by preparative TLC (30% EtOAc/hexane). The residue was dissolved in 1 mL of 4N HCl in dioxane (1 mL) and stirred for 2 h. The solvent was evaporated and the mixture was triturated with ether. The resulting solid was filtered, washed with ether (twice) and dried at 90° C. for 2 h. MS m/z 430 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.28-1.40 (m, 2H), 1.46-1.58 (m, 1H), 1.63-1.71 (m, 2H), 1.95-2.07 (m, 1H), 2.09-2.18 (m, 1H), 2.92-3.00 (m, 2H), 3.28-3.46 (m, 4H), 3.52-3.61 (m, 2H), 3.82-3.94 (m, 4H), 4.90-4.96 (m, 1H), 7.22-7.28 (m, 1H), 7.45 (s, 1H), 7.49-7.61 (m, 4H), 8.98 (s, 1H).

The following examples were prepared essentially as described above.

Ex. MS m/z # Name Mp (° C.) [M + H]⁺ Stereochemistry Salt Starting material 548 7-{[3-(tetrahydro-2H-pyran-4- 187-189 430 enantiomer 2 HCl 4- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)tetrahydro- 1,2,3,4,4a,9a- 2H-pyran hexahydro[1]benzofuro[2,3- c]pyridine 549 7-{[3-(prop-2-yn-1- 174-175 370 racemic HCl 3-bromoprop-1-yne yloxy)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 550 2-{[3-(1,2,3,4,4a,9a- 194-195 447 racemic HCl 2- hexahydro[1]benzofuro[2,3- (bromomethyl)benzonitrile c]pyridin-7- ylsulfonyl)phenoxy]methyl}benzonitrile 551 4-{[3-(1,2,3,4,4a,9a- 203-204 447 racemic HCl 4- hexahydro[1]benzofuro[2,3- (bromomethyl)benzonitrile c]pyridin-7- ylsulfonyl)phenoxy]methyl}benzonitrile 552 3-{[3-(1,2,3,4,4a,9a- 200-201 447 racemic HCl 3- hexahydro[1]benzofuro[2,3- (bromomethyl)benzonitrile c]pyridin-7- ylsulfonyl)phenoxy]methyl}benzonitrile 553 7-{[3-(tetrahydro-2H-pyran-2- 192-194 430 mixture of HCl 2- ylmethoxy)phenyl]sulfonyl}- diastereomers (bromomethyl)tetrahydro- 1,2,3,4,4a,9a- 2H-pyran hexahydro[1]benzofuro[2,3- c]pyridine 554 7-[(3-butoxyphenyl)sulfonyl]- 206-208 388 racemic HCl 1-bromobutane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 555 7-{[3- 208-210 386 racemic HCl (bromomethyl)cyclopropane (cyclopropylmethoxy)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 556 methyl 5-[3-(1,2,3,4,4a,9a- 179-181 446 racemic HCl methyl 5- hexahydro[1]benzofuro[2,3- bromopentanoate c]pyridin-7- ylsulfonyl)phenoxy]pentanoate 557 7-{[3-(pentyloxy)phenyl]sulfonyl}- 199-201 402 racemic HCl 1-bromopentane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 558 7-{[3-(2- 210-213 390 Racemic HCl 1-bromo-2- methoxyethoxy)phenyl]sulfonyl}- methoxyethane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 559 7-{[3-(pyridin-3- 167-171 423 racemic HCl 3- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)pyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 560 7-({3-[(1-methyl-1H-1,2,4-triazol- 187-190 427 racemic HCl 3-(bromomethyl)-1- 3-yl)methoxy]phenyl}sulfonyl)- methyl-1H-1,2,4- 1,2,3,4,4a,9a- triazole hexahydro[1]benzofuro[2,3- c]pyridine 561 7-{[3-(pyridin-4- 182-185 423 Racemic HCl 4- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)pyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 562 7-{[3-(pyridin-2- 179-182 423 racemic HCl 2- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)pyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 563 2-{3-[1,2,3,4,4a,9a- 237-239 389 Racemic HCl 2-bromoacetamide hexahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl]phenoxy}acetamide 564 2-{3-[1,2,3,4,4a,9a- 195-196 443 HCl 2-bromo-1-(pyrrolidin-1- hexahydro[1]benzofuro[2,3- yl)ethanone c]pyridin-7-ylsulfonyl]phenoxy}-1- (pyrrolidin-1-yl)ethanone 565 7-({3-[(5-methyl-1,2-oxazol-3- 215-217 427 racemic HCl 3-(bromomethyl)-5- yl)methoxy]phenyl}sulfonyl)- methyl-1,2-oxazole 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 566 7-{[2-methyl-3-(pyridin-3- 179-182 437 Racemic HCl 3- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)pyridine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 567 7-{[3-(pyrazin-2- 244-245 424 Racemic HCl 2- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)pyrazine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 568 3-{3-[1,2,3,4,4a,9a- 206-209 390 Racemic HCl 3-bromopropan-1-ol hexahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl]phenoxy}propan-1-ol 569 7-({3-[(2-methyl-1,3-thiazol-4- 205-208 443 Racemic HCl 4-(bromomethyl)-2- yl)methoxy]phenyl}sulfonyl)- methyl-1,3-thiazole 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 570 7-{[3-(tetrahydro-2H-pyran-4- 188-190 430 Racemic HCl 4- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)tetrahydro- 1,2,3,4,4a,9a- 2H-pyran hexahydro[1]benzofuro[2,3- c]pyridine 571 7-{[3-(tetrahydro-2H-pyran-4- 184-186 416 Racemic HCl 4-bromotetrahydro-2H- yloxy)phenyl]sulfonyl}- pyran 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 572 7-[(3-propoxyphenyl)sulfonyl]- 210-213 374 Racemic HCl 1-bromopropane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 573 7-({3-[2-(1H-pyrrol-1- 233-234 425 Racemic HCl 1-(2-bromoethyl)-1H- yl)ethoxy]phenyl}sulfonyl)- pyrrole 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 574 5-{3-[1,2,3,4,4a,9a- 189-190 413 Racemic HCl 5-bromopentanenitrile hexahydro[1]benzofuro[2,3- c]pyridin-7- ylsulfonyl]phenoxy}pentanenitrile 575 7-({3-[(3- 247-248 452 Racemic HCl 1-(bromomethyl)-3- methoxybenzyl)oxy]phenyl}sulfonyl)- methoxybenzene 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 576 7-{[3-(3- 179-181 404 Racemic HCl 1-bromo-3- methoxypropoxy)phenyl]sulfonyl}- methoxypropane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 577 7-{[3-(tetrahydrofuran-2- 205-206 416 Racemic, HCl 2- ylmethoxy)phenyl]sulfonyl}- mixture of (bromomethyl)tetrahydrofuran 1,2,3,4,4a,9a- diastereomers hexahydro[1]benzofuro[2,3- c]pyridine 578 7-{[3-(2,2- 263-266 396 racemic HCl 2-bromo-1,1- difluoroethoxy)phenyl]sulfonyl}- difluoroethane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 579 7-{[3-(pyridin-2- 198-203 409 Racemic HCl 2-bromopyridine yloxy)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 580 7-{[3-(pyrazin-2- 234-236 410 Racemic HCl 2-bromopyrazine yloxy)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 581 7-{[3-(tetrahydro-2H-pyran-4-   186-188C 430 enantiomer 1 HCl 4- ylmethoxy)phenyl]sulfonyl}- (bromomethyl)tetrahydro- 1,2,3,4,4a,9a- 2H-pyran hexahydro[1]benzofuro[2,3- c]pyridine 582 7-{[2-methyl-3-(tetrahydro-2H- 201-202 444 enantiomer 2 HCl 4- pyran-4- (bromomethyl)tetrahydro- ylmethoxy)phenyl]sulfonyl}- 2H-pyran 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 583 7-{[3-(cyclobutyloxy)-5- 218-220 416 racemic HCl bromocyclobutane methoxyphenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 584 7-{[3-methoxy-5-(tetrahydro-2H- 207-208 460 Racemic HCl 4- pyran-4- (bromomethyl)tetrahydro- ylmethoxy)phenyl]sulfonyl}- 2H-pyran 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 585 7-{[3-(cyclopropylmethoxy)-5- 224-225 416 Racemic HCl (bromomethyl)cyclopropane methoxyphenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 586 7-{[3-(cyclopentyloxy)-5- 239-241 430 racemic HCl bromocyclopentane methoxyphenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 587 7-[(3-butoxy-5- 418 racemic HCl 1-bromobutane methoxyphenyl)sulfonyl]- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 588 7-{[3-(3-methoxypropoxy)-5- 164-166 462 enantiomer 1 HCl 1-bromo-3- (propan-2-yloxy)phenyl]sulfonyl}- methoxypropane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 589 3-chloro-2-{3-[1,2,3,4,4a,9a- 211-213 482 Mixture of HCl 3-bromooxetane hexahydro[1]benzofuro[2,3- dec. diastereomers c]pyridin-7-ylsulfonyl]-5-(propan- 2-yloxy)phenoxy}propan-1-ol 590 2-{3-[1,2,3,4,4a,9a- 205-208 434 enantiomer 1 HCl (2-bromoethoxy)(tert- hexahydro[1]benzofuro[2,3- butyl)dimethylsilane c]pyridin-7-ylsulfonyl]-5-(propan- 2-yloxy)phenoxy}ethanol 591 7-{[3-fluoro-5-(tetrahydro-2H- 203-204 448 enantiomer 2 HCl 4- pyran-4- (bromomethyl)tetrahydro- ylmethoxy)phenyl]sulfonyl}- 2H-pyran 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 592 2-[7-(Phenylsulfonyl)-3,4-dihydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanol

A 0.50 N stock solution of 7-(phenylsulfonyl)-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine trifluoroacetate (1.12 g) and DIEA (1.8 mL, 4 eq) in DMF was prepared. To 500 μL (0.250 mmol) of this stock solution 1-bromoethanol (31 μL, 0.9 eq) was added. The reaction was stirred at 60° C. for 2 h. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. Conversion to the HCl salt was accomplished by dissolving the product in DCM, adding 2M HCl in Et₂O and evaporation of the solvent. MS m/z 358 [M+H]⁺.

The following examples were prepared essentially as described above.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 592 2-[7-(phenylsulfonyl)-3,4- 358 HCl 2-bromoethanol dihydro[1]benzofuro[2,3- c]pyridin-2(1H)-yl]ethanol 593 2-(2-methylpropyl)-7- 370 HCl 1-bromo-2- (phenylsulfonyl)-1,2,3,4- methylpropane tetrahydro[1]benzofuro[2,3- c]pyridine 594 2-(2-methoxyethyl)-7- 372 HCl 1-bromo-2- (phenylsulfonyl)-1,2,3,4- methoxyethane tetrahydro[1]benzofuro[2,3- c]pyridine 595 3-[7-(phenylsulfonyl)-3,4- 372 HCl 3-bromopropan-1-ol dihydro[1]benzofuro[2,3- c]pyridin-2(1H)-yl]propan-1- ol 596 2-(2-phenylethyl)-7- 418 HCl (2- (phenylsulfonyl)-1,2,3,4- bromoethyl)benzene tetrahydro[1]benzofuro[2,3- c]pyridine 597 2-benzyl-7- 404 HCl (bromomethyl)benzene (phenylsulfonyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 598 7-(phenylsulfonyl)-2-(2,2,2- 396 HCl 1,1,1-trifluoro-2- trifluoroethyl)-1,2,3,4- iodoethane tetrahydro[1]benzofuro[2,3- c]pyridine 599 2-{7-[(3- 392 HCl 2-bromoethanol chlorophenyl)sulfonyl]-3,4- dihydro[1]benzofuro[2,3- c]pyridin-2(1H)-yl}ethanol 600 7-[(3- 404 HCl 1-bromo-2- chlorophenyl)sulfonyl]-2-(2- methylpropane methylpropyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 601 3-{7-[(3- 406 HCl 3-bromopropan-1-ol chlorophenyl)sulfonyl]-3,4- dihydro[1]benzofuro[2,3- c]pyridin-2(1H)-yl}propan- 1-ol 602 7-[(3- 452 HCl (2- chlorophenyl)sulfonyl]-2-(2- bromoethyl)benzene phenylethyl)-1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 603 2-benzyl-7-[(3- 438 HCl (bromomethyl)benzene chlorophenyl)sulfonyl]- 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 604 7-[(3- 430 HCl 1,1,1-trifluoro-2- chlorophenyl)sulfonyl]-2- (2,2,2-trifluoroethyl)- iodoethane 1,2,3,4- tetrahydro[1]benzofuro[2,3- c]pyridine 605 2-ethyl-7-(phenylsulfonyl)- 344 Racemic TFA bromoethane 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 606 2-Cyclobutyl-7-(phenylsulfonyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine trifluoroacetic acid salt

A 0.20 N stock solution of 7-benzenesulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine trifluoroacetic acid salt and DIEA (2.5 eq) in anhydrous THF was prepared. 750 μL (0.150 mmol) of this amine stock solution and neat cyclobutanone (0.225 mmol) were combined. 450 μL (0.450 mmol) of a 1.0 N stock solution of acetic acid in anhydrous THF was added and the reaction was stirred at RT for 30 min. Sodium triacetoxyborohydride (95.4 mg, 0.450 mmol) was added last and the reaction was shaken at RT overnight. It was then quenched with aqueous saturated sodium bicarbonate solution (500 μL) to pH 6.0 and concentrated. Any remaining water was removed by azeotropic distillation with toluene. The crude product was purified by preparative LC/MS and concentrated to afford 7-benzenesulfonyl-2-cyclobutyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine as a trifluoroacetic acid salt. MS m/z 370 [M+H]⁺.

The following examples were prepared essentially as described above.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 606 2-cyclobutyl-7- 370 Racemic TFA cyclobutanone (phenylsulfonyl)- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 607 2-methyl-7- 330 Racemic TFA paraformaldehyde (phenylsulfonyl)- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 608 7-(phenylsulfonyl)-2- 358 Racemic HCl propan-2-one (propan-2-yl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 609 2-cyclopentyl-7- 384 Racemic TFA cyclopentanone (phenylsulfonyl)- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 610 2-cyclohexyl-7- 398 Racemic TFA cyclohexanone (phenylsulfonyl)- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 611 2-benzyl-7- 406 Racemic TFA benzaldehyde (phenylsulfonyl)- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 612 2-cyclobutyl-7-{[3-methoxy- 458 enantiomer 1 HCl cyclobutanone 5-(propan-2- yloxy)phenyl]sulfonyl}- 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine

Example 613 1-[7-(Phenylsulfonyl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanone

A 0.20 N stock solution of 7-benzenesulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine trifluoroacetic acid salt and DIEA (2.5 eq) in anhydrous THF was prepared. To 750 μL (0.150 mmol) of this stock solution, DIEA (39.2 μL, 0.225 mmol) and acetic anhydride (21.2 μL, 0.225 mmol) were added sequentially at RT. The reaction was shaken at room temperature overnight and concentrated. The crude product was purified by preparative LC/MS and concentrated to afford 1-[7-(phenylsulfonyl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanone as a trifluoroacetic acid salt. MS m/z 358 [M+H]⁺.

Example 614 1-[7-(Phenylsulfonyl)-3,4-dihydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanone trifluoroacetate

Prepared as described for Example 612 using 7-(phenylsulfonyl)-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (Example 343) and acetic anhydride. MS m/z 356 [M+H]⁺.

Example 615 1-{7-[(3-Chlorophenyl)sulfonyl]-3,4-dihydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl}ethanone

Prepared as described for Example 612 using 7-[(3-chlorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (Example 344) and acetic anhydride. MS m/z 390 [M+H]⁺.

Example 616 8-[(3-Fluorophenyl)sulfonyl]-1,4,5,10b-tetrahydro-2H-azeto[1,2-a][1]benzofuro[2,3-c]pyridine

3-Bromo-1,1-dimethoxypropane (27 uL, 1.5 eq) was added to a solution of {2-[6-(3-Fluoro-benzenesulfonyl)-benzofuran-3-yl]-ethyl}-carbamic acid tert-butyl ester (800 μL, 0.125 M) in DCE:TFA 1:1. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The crude product was purified by preparative LC/MS, concentrated, dissolved in DMF and DIEA (50 μL) was added. The reaction mixture was shaken at 50° C. for 2 h, purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. Conversion of the trifluoroacetic acid salt to the hydrochloric acid salt was performed by adding DCM followed by 2M HCl in ether and evaporation of the solvent. MS m/z 358 [M+H]⁺

The following examples were prepared essentially as described above and isolated as HCl salts

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Starting material 616 8-[(3-fluorophenyl)sulfonyl]- 358 racemic 3-bromo-1,1- 1,4,5,10b-tetrahydro-2H- dimethoxypropane azeto[1,2-a][1]benzofuro[2,3- c]pyridine 617 10-[(3-fluorophenyl)sulfonyl]- 386 racemic 2-(4-Bromo-butyl)- 1,3,4,6,7,12b-hexahydro-2H- [1,3]dioxolane [1]benzofuro[2,3-a]quinolizine 618 9-[(3-fluorophenyl)sulfonyl]- 386 racemic 2-(4-Bromo-butyl)- 1,3,4,6,7,12b-hexahydro-2H- [1,3]dioxolane [1]benzofuro[2,3-a]quinolizine 619 7-[(3-fluorophenyl)sulfonyl]- 358 racemic 3-bromo-1,1- 1,4,5,10b-tetrahydro-2H- dimethoxypropane azeto[1,2-a][1]benzofuro[2,3- c]pyridine 620 10-[(3-chlorophenyl)sulfonyl]- 402 racemic 2-(4-Bromo-butyl)- 1,3,4,6,7,12b-hexahydro-2H- [1,3]dioxolane [1]benzofuro[2,3-a]quinolizine 621 8-[(3-chlorophenyl)sulfonyl]- 374 racemic 3-bromo-1,1- 1,4,5,10b-tetrahydro-2H- dimethoxypropane azeto[1,2-a][1]benzofuro[2,3- c]pyridine

Example 622 7-{[3-(Propan-2-yloxy)phenyl]sulfonyl}-3,4,4a,9a-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,1′-cyclobutane]hydrochloride

A solution 7-{[3-(propan-2-yloxy)phenyl]sulfonyl}-3,4-dihydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,1′-cyclobutane]-2-carboxylic acid tert-butyl ester (0.050 g, 0.098 mmol) in MeOH was reduced at 30° C., 450 psi using a H-Cube® hydrogenator and a 10% Pd—C catalyst cartridge. After 50 min, the reaction mixture was concentrated and purified by silica gel column eluting with ethyl acetate/hexane. The residue was stirred in 4M HCl in dioxane for 1 h. Diethylether was added and the precipitate was filtered and dried under vacuum at 80° C. for 15 h to provide the title compound. MS m/z 414 [M+H]⁺. ¹H-NMR (400 MHz, CDCl3): δ 1.3 (d, J=6.2 Hz, 6H), 1.4 (m, 2H), 2.2 (m, 2H), 2.3-2.4 (m, 2H), 2.7 (m, 1H), 3.2 (m, 2H), 3.6-3.8 (m, 2H), 4.7 (m, 1H), 5.1 (d, J=6.7 Hz, 1H), 7.17 (m, 1H), 7.4-7.7 (m, 6H).

Example 623 7-[(3,5-Difluorophenyl)sulfonyl]-2′,3,3′,4,4a,5′,6′,9a-octahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran]hydrochloride

Prepared as described for Example 621 starting from 7-[(3,5-difluorophenyl)sulfonyl]-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran]-2-carboxylic acid tert-butyl ester. MS m/z 420 [M+H]⁺

Example 624 7-[(3-Fluorophenyl)sulfonyl]-1,1-dimethyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine

Prepared as described for Example 621 starting from 7-(3-fluoro-benzenesulfonyl)-1,1-dimethyl-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester. MS m/z 362 [M+]⁺

Example 625 7-[(3-Fluorophenyl)sulfinyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine trifluoroacetic acid salt

7-(3-Fluoro-phenylsulfanyl)-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (500 mg, 1 mmol) was dissolved into anhydrous methylene chloride (2.0 mL). (2R,3R)-2-Benzenesulfonyl-3-phenyl-oxaziridine (488 mg, 1.87 mmol) was added and the reaction was stirred at RT for 1.5 hours. The reaction solution was concentrated and the crude product was partially purified by preparative LC/MS. The resulting product was dissolved into methylene chloride (1.0 mL) and trifluoroacetic acid (1.0 mL). The reaction was shaken at RT for 15 minutes and concentrated. The crude product was purified by preparative LC/MS and concentrated to afford 7-[(3-fluorophenyl)sulfinyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine as a trifluoroacetic acid salt. MS m/z 318.0 [M+H]⁺.

Example 626 7-[(3-Fluoro-5-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy]phenyl)sulfonyl}-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine (Enantiomer 2)

Step 1 {6-[3-(3-Chloro-propoxy)-5-fluoro-benzenesulfonyl]-3-methyl-2,3-dihydro-benzofuran-2-ylmethyl}-methyl-carbamic acid tert-butyl ester (Enantiomer 2)

A mixture of 7-(3-fluoro-5-hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) and cesium carbonate (220 mg, 0.67 mmol) in acetonitrile (2 mL, 40 mmol) was stirred at 70° C. overnight. After 18 h the mixture was filtered through a pad of celite and was washed with dichloromethane. After solvent evaporation, the crude product was purified by preparative TLC (hexane:EtOAc 4:1) to provide desired product (120 mg).

Step 2 7-[(3-Fluoro-5-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)sulfonyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine (Enantiomer 2)

A mixture of 7-[3-(3-chloro-propoxy)-5-fluoro-benzenesulfonyl]-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol), (R)-2-methyl-pyrrolidine, benzenesulfonic acid salt (92.5 mg, 0.380 mmol), sodium iodide (28.5 mg, 0.190 mmol), potassium carbonate (78.8 mg, 0.570 mmol), N,N-diisopropylethylamine (99.3 uL, 0.570 mmol) in acetonitrile (8.04 mL, 154 mmol) was heated at 70° C. After 3 days the reaction was cooled to room temperature, diluted with 10 mL solvent (MeOH:CH₂Cl₂ 1:1) and filtered through a pad of silica-gel. The filtrate was concentrated. Purification by preparative TLC (MeOH:CH₂Cl₂ 1:9) followed by removal of N-Boc protecting group with 4N HCl using the general procedure described afforded the desired product. mp 208-212° C., MS m/z 475 [M+H]⁺. ¹H-NMR (400 MHz, DMSOd₆): δ 10.58 (br s, 1H), 9.52 (br s, 1H), 8.84 (br s, 1H), 7.58 (m, 2H), 7.49 (s, 1H), 7.43 (d, J=6.82 Hz, 1H), 7.34 (s, 1H), 7.22 (d, J=9.92 Hz, 1H), 4.95 (s, 1H), 4.19 (s, 2H), 4.03 (m, 1H), 3.58-3.31 (overlapping m & s, 4H), 3.04 (s, 2H), 2.94 (s, 2H), 2.16 (br s, 4H), 1.99 (s, 1H), 1.94 (br s, 2H), 1.40 (d, J=5.33 Hz, 3H), 1.17 (m, 2H).

Example 627 3-(1,2,3,4-Tetrahydro-benzo[4,5]furo[2,3-c]pyridine-7-sulfonyl)-phenol

Step 1 7-(3-Benzyloxy-benzenesulfonyl)-3,4-dihydro-1H-benzo[4, 5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Prepared as described for 7-(3-benzyloxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester using 7-iodo-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine and 3-benzyloxy-thiophenol

Step 2 3-(1,2,3,4-Tetrahydro-benzo[4,5]furo[2,3-c]pyridine-7-sulfonyl)-phenol

To a solution of 7-(3-benzyloxy-benzenesulfonyl)-3,4-dihydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol) in 5 mL methanol and 1 mL EtOAc was added Pd black (10% on carbon, 45 mg, 3.4 mmol). The mixture was kept under hydrogenation at 40 psi overnight and the solvent was evaporated. After filtration, the debenzylated product was taken to the next step without further purification. Removal of N-Boc protecting group with 4N HCl using a general procedure afforded the title product. mp 279-281° C., MS m/z 330 [M+H]⁺. ¹H-NMR (400 MHz, DMSOd₆): δ 10.26 (s, 1H), 9.76 (br s, 2H), 8.24 (s, 1H), 7.84 (m, 2H), 7.39 (m, 2H), 7.30 (s, 1H), 7.02 (m, 1H), 4.47 (s, 2H), 3.44 (m, 2H), 2.94 (m, 2H).

Example 628 3-[1,2,3,4,4a,9a-Hexahydro[1]benzofuro[2,3-c]pyridin-7-ylsulfonyl]phenyl ethylcarbamate

A mixture of 7-(3-hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (30 mg, 0.07 mmol), ethyl isocyanate (0.5 ml, excess) and triethylamine (0.5 mL, excess) was stirred at r.t. After 18 h, the mixture was filtered, and the filtrate evaporated. Purification by preparative TLC (hexane:EtOAc 40:60) followed by removal of N-Boc protecting group with 4N HCl using a general procedure afforded the title product. mp 217-219° C., MS m/z 403 [M+H]⁺. ¹H-NMR (400 MHz, DMSOd₆): δ 8.97 (br s, 1H), 7.80 (d, J=7.96 Hz, 1H), 7.62 (s, 1H), 7.60-7.55 (m, 3H), 7.43 (overlapping s and d, 2H), 4.95 (m, 1H), 3.57 (m, 2H), 3.44 (m, 1H), 3.14 (m, 2H), 2.94 (m; 2H), 2.55 (s, 2H), 2.12 (m, 1H), 1.52 (m, 1H), 1.09 (t, 3H).

Chiral Separations

The stereoisomers in the Table below were isolated from the corresponding stereoisomer mixture using SFC chromatography on a chiral column as described in the general method.

Ex. MS m/z # Name Mp (° C.) [M + H]⁺ Stereochemistry Salt Starting material 629 7-[(3- >200 402 Enantiomer 1 HCl Mixture of 7-[(3- fluorophenyl)sulfonyl]- fluorophenyl)sulfonyl]- 3,4,5′,6′-tetrahydro-2H,4′H- 3,4,5′,6′-tetrahydro-2H,4′H- spiro[1-benzofuro[2,3- spiro[1-benzofuro[2,3- c]pyridine-1,3′-pyran] c]pyridine-1,3′-pyran] 630 7-[(3- >200 402 Enantiomer 2 HCl Mixture of 7-[(3- fluorophenyl)sulfonyl]- fluorophenyl)sulfonyl]- 3,4,5′,6′-tetrahydro-2H,4′H- 3,4,5′,6′-tetrahydro-2H,4′H- spiro[1-benzofuro[2,3- spiro[1-benzofuro[2,3- c]pyridine-1,3′-pyran] c]pyridine-1,3′-pyran] 631 N-({7-[(3- 217-227 417 Enantiomer 1 HCl Mixture of N-({7-[(3- fluorophenyl)sulfonyl]-1- fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- tetrahydro[1]benzofuro[2,3- c]pyridin-1- c]pyridin-1- yl}methyl)acetamide yl}methyl)acetamide 632 N-({7-[(3- 210-260 417 Enantiomer 2 HCl Mixture of N-({7-[(3- fluorophenyl)sulfonyl]-1- fluorophenyl)sulfonyl]-1- methyl-1,2,3,4- methyl-1,2,3,4- tetrahydro[1]benzofuro[2,3- tetrahydro[1]benzofuro[2,3- c]pyridin-1- c]pyridin-1- yl}methyl)acetamide yl}methyl)acetamide 633 7-[(3- >200 390 Enantiomer 1 HCl Mixture of 7-[(3- fluorophenyl)sulfonyl]-1- fluorophenyl)sulfonyl]-1- (methoxymethyl)-1-methyl- (methoxymethyl)-1-methyl- 1,2,3,4- 1,2,3,4- tetrahydro[1]benzofuro[2,3- tetrahydro[1]benzofuro[2,3- c]pyridine c]pyridine 634 7-[(3- >200 390 Enantiomer 2 HCl Mixture of 7-[(3- fluorophenyl)sulfonyl]-1- fluorophenyl)sulfonyl]-1- (methoxymethyl)-1-methyl- (methoxymethyl)-1-methyl- 1,2,3,4- 1,2,3,4- tetrahydro[1]benzofuro[2,3- tetrahydro[1]benzofuro[2,3- c]pyridine c]pyridine

Example 635 1,2,3,4,4a,9a-Hexahydro[1]benzofuro[2,3-c]pyridin-7-yl 4-chlorobenzenesulfonate

A 0.2 M solution of tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (1.17 g) in DCM (20.1 mL) was prepared. To 300 μL of the 0.2 M solution of the phenol in DCM prepared above, DIEA (21 uL) was added followed by a 0.4 M solution of 4-chlorobenzenesulfonyl chloride (138 μL) in DCM. The reaction mixture was shaken for 16 h and TFA (500 μL) was added. After an additional 3 h of shaking the solvent was evaporated. Purification using preparative LC-MS afforded the title product as the trifluoroacetic acid salt. Conversion to the HCl salt was accomplished by dissolving the product in DCM, adding 2M HCl in Et₂O and evaporating the solvent. MS m/z 366 [M+H]⁺

The following examples were prepared essentially as described above.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 635 1,2,3,4,4a,9a- 366 racemic TFA 4-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4- chlorobenzenesulfonate 636 1,2,3,4,4a,9a- 332 racemic TFA benzenesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl benzenesulfonate 637 1,2,3,4,4a,9a- 346 racemic HCl phenylmethanesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl phenylmethanesulfonate 638 1,2,3,4,4a,9a- 412 racemic TFA 6-chloroimidazo[2,1- hexahydro[1]benzofuro[2,3- b][1,3]thiazole-5-sulfonyl c]pyridin-7-yl 6- chloride chloroimidazo[2,1- b][1,3]thiazole-5-sulfonate 639 1,2,3,4,4a,9a- 336 racemic TFA 1-methyl-1H-imidazole-4- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-7-yl 1-methyl-1H- imidazole-4-sulfonate 640 1,2,3,4,4a,9a- 337 racemic TFA 5-methyl-1,2-oxazole-4-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 5-methyl-1,2- oxazole-4-sulfonate 641 1,2,3,4,4a,9a- 346 racemic TFA 3-methylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3- methylbenzenesulfonate 642 1,2,3,4,4a,9a- 346 racemic TFA 4-methylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4- methylbenzenesulfonate 643 1,2,3,4,4a,9a- 350 racemic TFA 3-fluorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3- fluorobenzenesulfonate 644 1,2,3,4,4a,9a- 350 racemic TFA 4-fluorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4- fluorobenzenesulfonate 645 1,2,3,4,4a,9a- 350 racemic TFA 1,2-dimethyl-1H-imidazole-4- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-7-yl 1,2-dimethyl-1H- imidazole-4-sulfonate 646 1,2,3,4,4a,9a- 351 racemic TFA 3,5-dimethyl-1,2-oxazole-4- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-7-yl 3,5-dimethyl-1,2- oxazole-4-sulfonate 647 1,2,3,4,4a,9a- 360 racemic TFA 2,5-dimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 2,5- dimethylbenzenesulfonate 648 1,2,3,4,4a,9a- 360 racemic TFA 3,5-dimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3,5- dimethylbenzenesulfonate 649 1,2,3,4,4a,9a- 360 racemic TFA 3,4-dimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3,4- dimethylbenzenesulfonate 650 1,2,3,4,4a,9a- 362 racemic TFA 4-methoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4- methoxybenzenesulfonate 651 1,2,3,4,4a,9a- 362 racemic TFA 3-methoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3- methoxybenzenesulfonate 652 1,2,3,4,4a,9a- 364 racemic TFA 3-fluoro-4- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-7-yl 3-fluoro-4- methylbenzenesulfonate 653 1,2,3,4,4a,9a- 366 racemic TFA 3-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3- chlorobenzenesulfonate 654 1,2,3,4,4a,9a- 366 racemic TFA 2-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 2- chlorobenzenesulfonate 655 1,2,3,4,4a,9a- 372 racemic TFA 1-benzofuran-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 1-benzofuran-2- sulfonate 656 1,2,3,4,4a,9a- 374 racemic TFA 2,4,6-trimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 2,4,6- trimethylbenzenesulfonate 657 1,2,3,4,4a,9a- 374 racemic TFA 4-(propan-2-yl)benzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4-(propan-2- yl)benzenesulfonate 658 1,2,3,4,4a,9a- 380 racemic TFA 3-chloro-2- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-7-yl 3-chloro-2- methylbenzenesulfonate 659 1,2,3,4,4a,9a- 380 racemic TFA 3-chloro-4- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-7-yl 3-chloro-4- methylbenzenesulfonate 660 1,2,3,4,4a,9a- 382 racemic TFA naphthalene-1-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl naphthalene-1- sulfonate 661 1,2,3,4,4a,9a- 382 racemic TFA naphthalene-2-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl naphthalene-2- sulfonate 662 1,2,3,4,4a,9a- 383 racemic TFA quinoline-8-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl quinoline-8- sulfonate 663 1,2,3,4,4a,9a- 384 racemic TFA 3-chloro-4- hexahydro[1]benzofuro[2,3- fluorobenzenesulfonyl chloride c]pyridin-7-yl 3-chloro-4- fluorobenzenesulfonate 664 1,2,3,4,4a,9a- 388 racemic TFA 1-benzothiophene-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 1- benzothiophene-2-sulfonate 665 1,2,3,4,4a,9a- 388 racemic TFA 1-benzothiophene-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 1- benzothiophene-3-sulfonate 666 1,2,3,4,4a,9a- 388 racemic TFA 4-tert-butylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4-tert- butylbenzenesulfonate 667 1,2,3,4,4a,9a- 389 racemic TFA 4- hexahydro[1]benzofuro[2,3- (acetylamino)benzenesulfonyl c]pyridin-7-yl 4- chloride (acetylamino)benzenesulfonate 668 1,2,3,4,4a,9a- 390 racemic TFA 2,3-dihydro-1,4-benzodioxine- hexahydro[1]benzofuro[2,3- 6-sulfonyl chloride c]pyridin-7-yl 2,3-dihydro-1,4- benzodioxine-6-sulfonate 669 1,2,3,4,4a,9a- 390 racemic TFA 2,1,3-benzothiadiazole-4- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-7-yl 2,1,3- benzothiadiazole-4-sulfonate 670 1,2,3,4,4a,9a- 392 racemic TFA 2,5-dimethoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 2,5- dimethoxybenzenesulfonate 671 1,2,3,4,4a,9a- 398 racemic TFA 4-(1H-pyrazol-1- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl chloride c]pyridin-7-yl 4-(1H-pyrazol-1- yl)benzenesulfonate 672 1,2,3,4,4a,9a- 399 racemic TFA 4-(1,3-oxazol-5- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl chloride c]pyridin-7-yl 4-(1,3-oxazol-5- yl)benzenesulfonate 673 1,2,3,4,4a,9a- 400 racemic TFA 4- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-7-yl 4- chloride (trifluoromethyl)benzenesulfonate 674 1,2,3,4,4a,9a- 400 racemic TFA 2- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-7-yl 2- chloride (trifluoromethyl)benzenesulfonate 675 1,2,3,4,4a,9a- 400 racemic TFA 3- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-7-yl 3- chloride (trifluoromethyl)benzenesulfonate 676 1,2,3,4,4a,9a- 400 racemic TFA 3,4-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3,4- dichlorobenzenesulfonate 677 1,2,3,4,4a,9a- 400 racemic TFA 3,5-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 3,5- dichlorobenzenesulfonate 678 1,2,3,4,4a,9a- 400 racemic TFA 2,3-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 2,3- dichlorobenzenesulfonate 679 1,2,3,4,4a,9a- 400 racemic TFA 2,6-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 2,6- dichlorobenzenesulfonate 680 1,2,3,4,4a,9a- 405 racemic TFA 5-(1,2-oxazol-3-yl)thiophene-2- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-7-yl 5-(1,2-oxazol-3- yl)thiophene-2-sulfonate 681 1,2,3,4,4a,9a- 408 racemic TFA biphenyl-4-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl biphenyl-4- sulfonate 682 1,2,3,4,4a,9a- 416 racemic TFA 4- hexahydro[1]benzofuro[2,3- (trifluoromethoxy)benzenesulfonyl c]pyridin-7-yl 4- chloride (trifluoromethoxy)benzenesulfonate 683 1,2,3,4,4a,9a- 418 racemic TFA 6-(morpholin-4-yl)pyridine-3- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-7-yl 6-(morpholin-4- yl)pyridine-3-sulfonate 684 1,2,3,4,4a,9a- 383 racemic TFA isoquinoline-5-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl isoquinoline-5- sulfonate 685 1,2,3,4,4a,9a- 425 racemic TFA 6-phenoxypyridine-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 6- phenoxypyridine-3-sulfonate 686 1,2,3,4,4a,9a- 482 racemic TFA 4-phenyl-5- hexahydro[1]benzofuro[2,3- (trifluoromethyl)thiophene-3- c]pyridin-7-yl 4-phenyl-5- sulfonyl chloride (trifluoromethyl)thiophene-3- sulfonate 687 1,2,3,4,4a,9a- 436 racemic TFA 5-chloro-3-methyl-1- hexahydro[1]benzofuro[2,3- benzothiophene-2-sulfonyl c]pyridin-7-yl 5-chloro-3- chloride methyl-1-benzothiophene-2- sulfonate 688 1,2,3,4,4a,9a- 377 racemic TFA 4-nitrobenzenesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl 4- nitrobenzenesulfonate 689 1,2,3,4,4a,9a- 333 racemic TFA pyridine-2-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl pyridine-2- sulfonate 690 1,2,3,4,4a,9a- 352 racemic TFA cyclohexylmethanesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl cyclohexylmethanesulfonate 691 1,2,3,4,4a,9a- 360 racemic TFA 2-phenylethanesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-7-yl 2- phenylethanesulfonate 692 1,2,3,4,4a,9a- 412 racemic HCl 6-chloroimidazo[2,1- hexahydro[1]benzofuro[2,3- b][1,3]thiazole-5-sulfonyl c]pyridin-7-yl 6- chloride chloroimidazo[2,1- b][1,3]thiazole-5-sulfonate 693 1,2,3,4,4a,9a- 374 racemic HCl 4-(propan-2-yl)benzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-7-yl 4-(propan-2- yl)benzenesulfonate 694 1,2,3,4,4a,9a- 436 racemic HCl 5-chloro-3-methyl-1- hexahydro[1]benzofuro[2,3- benzothiophene-2-sulfonyl c]pyridin-7-yl 5-chloro-3- chloride methyl-1-benzothiophene-2- sulfonate 695 1,2,3,4,4a,9a- 366 racemic HCl 4-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4- chlorobenzenesulfonate 696 1,2,3,4,4a,9a- 332 racemic TFA benzenesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl benzenesulfonate 697 1,2,3,4,4a,9a- 346 racemic TFA phenylmethanesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl phenylmethanesulfonate 698 1,2,3,4,4a,9a- 412 racemic TFA 6-chloroimidazo[2,1- hexahydro[1]benzofuro[2,3- b][1,3]thiazole-5-sulfonyl c]pyridin-6-yl 6- chloride chloroimidazo[2,1- b][1,3]thiazole-5-sulfonate 699 1,2,3,4,4a,9a- 346 racemic TFA 3-methylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3- methylbenzenesulfonate 700 1,2,3,4,4a,9a- 346 racemic TFA 4-methylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4- methylbenzenesulfonate 701 1,2,3,4,4a,9a- 350 racemic TFA 3-fluorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3- fluorobenzenesulfonate 702 1,2,3,4,4a,9a- 350 racemic TFA 4-fluorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4- fluorobenzenesulfonate 703 1,2,3,4,4a,9a- 351 racemic TFA 3,5-dimethyl-1,2-oxazole-4- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-6-yl 3,5-dimethyl-1,2- oxazole-4-sulfonate 704 1,2,3,4,4a,9a- 360 racemic TFA 2,5-dimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2,5- dimethylbenzenesulfonate 705 1,2,3,4,4a,9a- 360 racemic TFA 3,5-dimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3,5- dimethylbenzenesulfonate 706 1,2,3,4,4a,9a- 360 racemic TFA 3,4-dimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3,4- dimethylbenzenesulfonate 707 1,2,3,4,4a,9a- 362 racemic TFA 4-methoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4- methoxybenzenesulfonate 708 1,2,3,4,4a,9a- 362 racemic TFA 3-methoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3- methoxybenzenesulfonate 709 1,2,3,4,4a,9a- 364 racemic TFA 3-fluoro-4- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-6-yl 3-fluoro-4- methylbenzenesulfonate 710 1,2,3,4,4a,9a- 366 racemic TFA 3-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3- chlorobenzenesulfonate 711 1,2,3,4,4a,9a- 366 racemic TFA 2-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2- chlorobenzenesulfonate 712 1,2,3,4,4a,9a- 368 racemic TFA 2,4-difluorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2,4- difluorobenzenesulfonate 713 1,2,3,4,4a,9a- 372 racemic TFA 1-benzofuran-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1-benzofuran-2- sulfonate 714 1,2,3,4,4a,9a- 372 racemic TFA 1-benzofuran-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1-benzofuran-2- sulfonate 715 1,2,3,4,4a,9a- 374 racemic TFA 2,4,6-trimethylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2,4,6- trimethylbenzenesulfonate 716 1,2,3,4,4a,9a- 374 racemic TFA 4-(propan-2-yl)benzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4-(propan-2- yl)benzenesulfonate 717 1,2,3,4,4a,9a- 380 racemic TFA 3-chloro-2- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-6-yl 3-chloro-2- methylbenzenesulfonate 718 1,2,3,4,4a,9a- 380 racemic TFA 3-chloro-2- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-6-yl 3-chloro-2- methylbenzenesulfonate 719 1,2,3,4,4a,9a- 380 racemic TFA 3-chloro-4- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-6-yl 3-chloro-4- methylbenzenesulfonate 720 1,2,3,4,4a,9a- 382 racemic TFA naphthalene-1-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl naphthalene-1- sulfonate 721 1,2,3,4,4a,9a- 382 racemic TFA naphthalene-2-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl naphthalene-2- sulfonate 722 1,2,3,4,4a,9a- 383 racemic TFA quinoline-8-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl quinoline-8- sulfonate 723 1,2,3,4,4a,9a- 384 racemic TFA 3-chloro-4- hexahydro[1]benzofuro[2,3- fluorobenzenesulfonyl chloride c]pyridin-6-yl 3-chloro-4- fluorobenzenesulfonate 724 1,2,3,4,4a,9a- 388 racemic TFA 1-benzothiophene-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1- benzothiophene-2-sulfonate 725 1,2,3,4,4a,9a- 388 racemic TFA 1-benzothiophene-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1- benzothiophene-3-sulfonate 726 1,2,3,4,4a,9a- 388 racemic TFA 1-benzothiophene-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1- benzothiophene-3-sulfonate 727 1,2,3,4,4a,9a- 388 racemic TFA 4-tert-butylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4-tert- butylbenzenesulfonate 728 1,2,3,4,4a,9a- 389 racemic TFA 4- hexahydro[1]benzofuro[2,3- (acetylamino)benzenesulfonyl c]pyridin-6-yl 4- chloride (acetylamino)benzenesulfonate 729 1,2,3,4,4a,9a- 390 racemic TFA 2,3-dihydro-1,4-benzodioxine- hexahydro[1]benzofuro[2,3- 6-sulfonyl chloride c]pyridin-6-yl 2,3-dihydro-1,4- benzodioxine-6-sulfonate 730 1,2,3,4,4a,9a- 390 racemic TFA 2,1,3-benzothiadiazole-4- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-6-yl 2,1,3- benzothiadiazole-4-sulfonate 731 1,2,3,4,4a,9a- 392 racemic TFA 2,5-dimethoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2,5- dimethoxybenzenesulfonate 732 1,2,3,4,4a,9a- 392 racemic TFA 3,4-dimethoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3,4- dimethoxybenzenesulfonate 733 1,2,3,4,4a,9a- 398 racemic TFA 4-(1H-pyrazol-1- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl chloride c]pyridin-6-yl 4-(1H-pyrazol-1- yl)benzenesulfonate 734 1,2,3,4,4a,9a- 399 racemic TFA 4-(1,3-oxazol-5- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl chloride c]pyridin-6-yl 4-(1,3-oxazol-5- yl)benzenesulfonate 735 1,2,3,4,4a,9a- 400 racemic TFA 4- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-6-yl 4- chloride (trifluoromethyl)benzenesulfonate 736 1,2,3,4,4a,9a- 400 racemic TFA 2- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-6-yl 2- chloride (trifluoromethyl)benzenesulfonate 737 1,2,3,4,4a,9a- 400 racemic TFA 3- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-6-yl 3- chloride (trifluoromethyl)benzenesulfonate 738 1,2,3,4,4a,9a- 400 racemic TFA 3,4-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3,4- dichlorobenzenesulfonate 739 1,2,3,4,4a,9a- 400 racemic TFA 3,5-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3,5- dichlorobenzenesulfonate 740 1,2,3,4,4a,9a- 400 racemic TFA 2,3-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2,3- dichlorobenzenesulfonate 741 1,2,3,4,4a,9a- 400 racemic TFA 2,6-dichlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2,6- dichlorobenzenesulfonate 742 1,2,3,4,4a,9a- 405 racemic TFA 5-(1,2-oxazol-3-yl)thiophene-2- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-6-yl 5-(1,2-oxazol-3- yl)thiophene-2-sulfonate 743 1,2,3,4,4a,9a- 408 racemic TFA biphenyl-4-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl biphenyl-4- sulfonate 744 1,2,3,4,4a,9a- 416 racemic TFA 4- hexahydro[1]benzofuro[2,3- (trifluoromethoxy)benzenesulfonyl c]pyridin-6-yl 4- chloride (trifluoromethoxy)benzenesulfonate 745 1,2,3,4,4a,9a- 383 racemic TFA isoquinoline-5-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl isoquinoline-5- sulfonate 746 1,2,3,4,4a,9a- 425 racemic TFA 6-phenoxypyridine-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 6- phenoxypyridine-3-sulfonate 747 1,2,3,4,4a,9a- 482 racemic TFA 4-phenyl-5- hexahydro[1]benzofuro[2,3- (trifluoromethyl)thiophene-3- c]pyridin-6-yl 4-phenyl-5- sulfonyl chloride (trifluoromethyl)thiophene-3- sulfonate 748 1,2,3,4,4a,9a- 436 racemic TFA 5-chloro-3-methyl-1- hexahydro[1]benzofuro[2,3- benzothiophene-2-sulfonyl c]pyridin-6-yl 5-chloro-3- chloride methyl-1-benzothiophene-2- sulfonate 749 1,2,3,4,4a,9a- 377 racemic TFA 4-nitrobenzenesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl 4- nitrobenzenesulfonate 750 1,2,3,4,4a,9a- 414 racemic TFA [3- hexahydro[1]benzofuro[2,3- (trifluoromethyl)phenyl]methanesulfonyl c]pyridin-6-yl [3- chloride (trifluoromethyl)phenyl]methanesulfonate 751 1,2,3,4,4a,9a- 414 racemic TFA [4- hexahydro[1]benzofuro[2,3- (trifluoromethyl)phenyl]methanesulfonyl c]pyridin-6-yl [4- chloride (trifluoromethyl)phenyl]methanesulfonate 752 1,2,3,4,4a,9a- 380 racemic TFA (3- hexahydro[1]benzofuro[2,3- chlorophenyl)methanesulfonyl c]pyridin-6-yl (3- chloride chlorophenyl)methanesulfonate 753 1,2,3,4,4a,9a- 333 racemic TFA pyridine-2-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl pyridine-2- sulfonate 754 1,2,3,4,4a,9a- 380 racemic TFA (2- hexahydro[1]benzofuro[2,3- chlorophenyl)methanesulfonyl c]pyridin-6-yl (2- chloride chlorophenyl)methanesulfonate 755 1,2,3,4,4a,9a- 360 racemic TFA 2-phenylethanesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl 2- phenylethanesulfonate 756 1,2,3,4,4a,9a- 382 racemic TFA (2,4- hexahydro[1]benzofuro[2,3- difluorophenyl)methanesulfonyl c]pyridin-6-yl (2,4- chloride difluorophenyl)methanesulfonate 757 4a-methyl-1,2,3,4,4a,9a- 380 racemic TFA 4-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4- chlorobenzenesulfonate 758 4a-methyl-1,2,3,4,4a,9a- 360 racemic HCl phenylmethanesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl phenylmethanesulfonate 759 4a-methyl-1,2,3,4,4a,9a- 346 racemic HCl benzenesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl benzenesulfonate 760 4a-methyl-1,2,3,4,4a,9a- 376 racemic TFA 4-methoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4- methoxybenzenesulfonate 761 4a-methyl-1,2,3,4,4a,9a- 376 racemic TFA 3-methoxybenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3- methoxybenzenesulfonate 762 4a-methyl-1,2,3,4,4a,9a- 380 racemic TFA 3-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 3- chlorobenzenesulfonate 763 4a-methyl-1,2,3,4,4a,9a- 380 racemic TFA 2-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 2- chlorobenzenesulfonate 764 4a-methyl-1,2,3,4,4a,9a- 386 racemic TFA 1-benzofuran-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1-benzofuran-2- sulfonate 765 4a-methyl-1,2,3,4,4a,9a- 386 racemic TFA 1-benzofuran-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1-benzofuran-2- sulfonate 766 4a-methyl-1,2,3,4,4a,9a- 388 racemic TFA 4-(propan-2-yl)benzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4-(propan-2- yl)benzenesulfonate 767 4a-methyl-1,2,3,4,4a,9a- 394 racemic TFA 3-chloro-2- hexahydro[1]benzofuro[2,3- methylbenzenesulfonyl chloride c]pyridin-6-yl 3-chloro-2- methylbenzenesulfonate 768 4a-methyl-1,2,3,4,4a,9a- 396 racemic TFA naphthalene-1-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl naphthalene-1- sulfonate 769 4a-methyl-1,2,3,4,4a,9a- 396 racemic TFA naphthalene-2-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl naphthalene-2- sulfonate 770 4a-methyl-1,2,3,4,4a,9a- 397 racemic TFA quinoline-8-sulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl quinoline-8- sulfonate 771 4a-methyl-1,2,3,4,4a,9a- 402 racemic TFA 1-benzothiophene-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1- benzothiophene-3-sulfonate 772 4a-methyl-1,2,3,4,4a,9a- 402 racemic TFA 1-benzothiophene-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1- benzothiophene-3-sulfonate 773 4a-methyl-1,2,3,4,4a,9a- 402 racemic TFA 1-benzothiophene-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 1- benzothiophene-2-sulfonate 774 4a-methyl-1,2,3,4,4a,9a- 402 racemic TFA 4-tert-butylbenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 4-tert- butylbenzenesulfonate 775 4a-methyl-1,2,3,4,4a,9a- 404 racemic TFA 2,3-dihydro-1,4-benzodioxine- hexahydro[1]benzofuro[2,3- 6-sulfonyl chloride c]pyridin-6-yl 2,3-dihydro-1,4- benzodioxine-6-sulfonate 776 4a-methyl-1,2,3,4,4a,9a- 412 racemic TFA 4-(1H-pyrazol-1- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl chloride c]pyridin-6-yl 4-(1H-pyrazol-1- yl)benzenesulfonate 777 4a-methyl-1,2,3,4,4a,9a- 413 racemic TFA 4-(1,3-oxazol-5- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl chloride c]pyridin-6-yl 4-(1,3-oxazol-5- yl)benzenesulfonate 778 4a-methyl-1,2,3,4,4a,9a- 414 racemic TFA 4- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-6-yl 4- chloride (trifluoromethyl)benzenesulfonate 779 4a-methyl-1,2,3,4,4a,9a- 414 racemic TFA 2- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-6-yl 2- chloride (trifluoromethyl)benzenesulfonate 780 4a-methyl-1,2,3,4,4a,9a- 414 racemic TFA 3- hexahydro[1]benzofuro[2,3- (trifluoromethyl)benzenesulfonyl c]pyridin-6-yl 3- chloride (trifluoromethyl)benzenesulfonate 781 4a-methyl-1,2,3,4,4a,9a- 419 racemic TFA 5-(1,2-oxazol-3-yl)thiophene-2- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-6-yl 5-(1,2-oxazol-3- yl)thiophene-2-sulfonate 782 4a-methyl-1,2,3,4,4a,9a- 439 racemic TFA 6-phenoxypyridine-3-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl 6- phenoxypyridine-3-sulfonate 783 4a-methyl-1,2,3,4,4a,9a- 450 racemic TFA 5-chloro-3-methyl-1- hexahydro[1]benzofuro[2,3- benzothiophene-2-sulfonyl c]pyridin-6-yl 5-chloro-3- chloride methyl-1-benzothiophene-2- sulfonate 784 4a-methyl-1,2,3,4,4a,9a- 394 racemic TFA (2- hexahydro[1]benzofuro[2,3- chlorophenyl)methanesulfonyl c]pyridin-6-yl (2- chloride chlorophenyl)methanesulfonate 785 4a-methyl-1,2,3,4,4a,9a- 374 racemic TFA 2-phenylethanesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl 2- phenylethanesulfonate 786 4a-methyl-1,2,3,4,4a,9a- 378 racemic TFA (2- hexahydro[1]benzofuro[2,3- fluorophenyl)methanesulfonyl c]pyridin-6-yl (2- chloride fluorophenyl)methanesulfonate 787 4a-methyl-1,2,3,4,4a,9a- 396 racemic TFA (2,4- hexahydro[1]benzofuro[2,3- difluorophenyl)methanesulfonyl c]pyridin-6-yl (2,4- chloride difluorophenyl)methanesulfonate 788 4a-methyl-1,2,3,4,4a,9a- 428 racemic TFA [3- hexahydro[1]benzofuro[2,3- (trifluoromethyl)phenyl]methanesulfonyl c]pyridin-6-yl [3- chloride (trifluoromethyl)phenyl]methanesulfonate 789 4a-methyl-1,2,3,4,4a,9a- 394 racemic TFA (4- hexahydro[1]benzofuro[2,3- chlorophenyl)methanesulfonyl c]pyridin-6-yl (4- chloride chlorophenyl)methanesulfonate 790 4a-methyl-1,2,3,4,4a,9a- 378 racemic TFA (4- hexahydro[1]benzofuro[2,3- fluorophenyl)methanesulfonyl c]pyridin-6-yl (4- chloride fluorophenyl)methanesulfonate 791 4a-methyl-1,2,3,4,4a,9a- 394 racemic TFA (3- hexahydro[1]benzofuro[2,3- chlorophenyl)methanesulfonyl c]pyridin-6-yl (3- chloride chlorophenyl)methanesulfonate Chiral Separations

The stereoisomers in the Table below were isolated from the corresponding stereoisomer mixture using SFC chromatography on a chiral column as described in the general method.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 792 1,2,3,4,4a,9a- 412 enantiomer 1 HCl Example 692 hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 6-chloroimidazo[2,1- b][1,3]thiazole-5-sulfonate 793 1,2,3,4,4a,9a- 412 enantiomer 2 HCl Example 692 hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 6-chloroimidazo[2,1- b][1,3]thiazole-5-sulfonate 794 1,2,3,4,4a,9a- 374 enantiomer 1 HCl Example 693 hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-(propan-2-yl)benzenesulfonate 795 1,2,3,4,4a,9a- 374 enantiomer 2 HCl Example 693 hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-(propan-2-yl)benzenesulfonate 796 1,2,3,4,4a,9a- 436 enantiomer 1 HCl Example 694 hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 5-chloro-3-methyl-1- benzothiophene-2-sulfonate 797 1,2,3,4,4a,9a- 436 enantiomer 2 HCl Example 694 hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 5-chloro-3-methyl-1- benzothiophene-2-sulfonate

Example 798 2-(Propan-2-yl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-7-yl-4-chlorobenzenesulfonate

Prepared as described for 2-cyclobutyl-7-(phenylsulfonyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine (Example 606) starting from 1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-7-yl 4-chlorobenzenesulfonate (example 634) and propan-2-one. MS m/z 408 [M+H]⁺

The following examples were prepared essentially as described above. All compounds were isolated as TFA salts.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Starting material 798 2-(propan-2-yl)-1,2,3,4,4a,9a- 408 racemic propan-2-one hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-chlorobenzenesulfonate 799 2-methyl-1,2,3,4,4a,9a- 380 racemic paraformaldehyde hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-chlorobenzenesulfonate 800 2-cyclobutyl-1,2,3,4,4a,9a- 420 racemic cyclobutanone hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-chlorobenzenesulfonate 801 2-cyclopentyl-1,2,3,4,4a,9a- 434 racemic cyclopentanone hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-chlorobenzenesulfonate 802 2-cyclohexyl-1,2,3,4,4a,9a- 448 racemic cyclohexanone hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-chlorobenzenesulfonate 803 2-benzyl-1,2,3,4,4a,9a- 456 racemic benzaldehyde hexahydro[1]benzofuro[2,3-c]pyridin- 7-yl 4-chlorobenzenesulfonate 804 4a-methyl-2-(propan-2-yl)- 402 racemic propan-2-one 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3-c]pyridin- 6-yl phenylmethanesulfonate 805 2-cyclobutyl-4a-methyl-1,2,3,4,4a,9a- 414 racemic cyclobutanone hexahydro[1]benzofuro[2,3-c]pyridin- 6-yl phenylmethanesulfonate 806 2-cyclopentyl-4a-methyl- 428 racemic cyclopentanone 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3-c]pyridin- 6-yl phenylmethanesulfonate 807 2-cyclohexyl-4a-methyl- 442 racemic cyclohexanone 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3-c]pyridin- 6-yl phenylmethanesulfonate 808 2-benzyl-4a-methyl-1,2,3,4,4a,9a- 450 racemic benzaldehyde hexahydro[1]benzofuro[2,3-c]pyridin- 6-yl phenylmethanesulfonate 809 2,4a-dimethyl-1,2,3,4,4a,9a- 374 racemic paraformaldehyde hexahydro[1]benzofuro[2,3-c]pyridin- 6-yl phenylmethanesulfonate

Example 810 2-Ethyl-4a-methyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-6-yl phenylmethanesulfonate

Prepared as described for 2-[7-(phenylsulfonyl)-3,4-dihydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanol (Example 592) starting from 4a-methyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-6-yl phenylmethanesulfonate (Example 757) and bromoethane. MS m/z 388 [M+H]⁺

The following examples were prepared essentially as described described above. All compounds were isolated as TFA salts.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Starting material 810 2-ethyl-4a-methyl-1,2,3,4,4a,9a- 388 racemic bromoethane hexahydro[1]benzofuro[2,3-c]pyridin-6- yl phenylmethanesulfonate 811 4a-methyl-2-(2-phenylethyl)- 464 racemic (2- 1,2,3,4,4a,9a- bromoethyl)benzene hexahydro[1]benzofuro[2,3-c]pyridin-6- yl phenylmethanesulfonate 812 2-ethyl-1,2,3,4,4a,9a- 394 racemic bromoethane hexahydro[1]benzofuro[2,3-c]pyridin-7- yl 4-chlorobenzenesulfonate 813 2-(2-phenylethyl)-1,2,3,4,4a,9a- 470 racemic (2- hexahydro[1]benzofuro[2,3-c]pyridin-7- bromoethyl)benzene yl 4-chlorobenzenesulfonate

Example 814 N-(2-Acetyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-6-yl)naphthalene-2-sulfonamide

Step 1 1-(3,4,4a,9a-Tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone

3,4,4a,9a-Tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester was prepared as described for tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from N-Boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromophenol. Then 3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (4.5 g, 16.6 mmol) was stirred in 4M HCl in dioxane (70 mL). The solvent was evaporated, diethylether was added, and the resulting solid was filtered, washed with diethylether and dried to provide the amine as an hydrochloric acid salt.

To a mixture of 3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine hydrochloride (3.2 g, 15.1 mmol) and sodium hydrogenocarbonate (14 g) in chloroform (40 mL), was slowly added a solution of acetyl chloride (1.5 mL, 21 mmol) in chloroform (5 mL). After stirring for 2 h another portion of acetyl chloride was added. After 5 h the solvent was evaporated. Purification using silica gel chromatography (78 g SiO₂) eluting with ethyl acetate yielded 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone.

Step 2 1-(6-Amino-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone

Fuming (90%) nitric acid (2.9 g) was added to 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (2.7 g, 12.5 mmol). The reaction mixture was stirred at 85° C. for 2 h, poured into H₂O (350 mL) and the product was extracted with DCM (3×). The combined organic layers were washed with sodium hydrogenocarbonate and brine, and solvent was evaporated. Purification using silica gel chromatography (150 g SiO₂) eluting with ethyl acetate yielded 1-(6-nitro-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone.

A mixture of 1-(6-nitro-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (600 mg) in MeOH (60 mL) was hydrogenated for 16 h at 10 bar using a H-Cube® instrument with a 70 mm cartridge of 10% Pd—C. The solvent was evaporated to yield 1-(6-amino-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone. MS m/z 233 [M+H]⁺

Step 3 N-(2-Acetyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-6-yl)naphthalene-2-sulfonamide

A 0.5 M solution of 1-(6-amino-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (557 mg) in DCE (4.8 mL) was prepared. To 1.2 mL of the 0.5 M solution of aniline in DCM prepared above, was added DIEA (215 μL) followed by naphthalene-2-sulfonyl chloride (125 mg). The reaction mixture was shaken for 16 h and the solvent was evaporated. A portion of the residue was purified by preparative LC-MS. MS m/z 423 [M+H]⁺

The following examples were prepared essentially as described above.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Starting material 814 N-(2-acetyl-1,2,3,4,4a,9a- 423 racemic naphthalene-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)naphthalene-2- sulfonamide 815 N-(2-acetyl-1,2,3,4,4a,9a- 401 Racemic 2,5- hexahydro[1]benzofuro[2,3- dimethylbenzenesulfonyl c]pyridin-6-yl)-2,5- chloride dimethylbenzenesulfonamide 816 N-(2-acetyl-1,2,3,4,4a,9a- 453 racemic 6-chloroimidazo[2,1- hexahydro[1]benzofuro[2,3- b][1,3]thiazole-5-sulfonyl c]pyridin-6-yl)-6-chloroimidazo[2,1- chloride b][1,3]thiazole-5-sulfonamide

Example 817 N-(1,2,3,4,4a,9a-Hexahydro[1]benzofuro[2,3-c]pyridin-6-yl)benzenesulfonamide

Prepared as described in step 2 of Example 813 except that benzensulfonylchloride was used instead of naphthalene-2-sulfonyl chloride. The crude product was dissolved in dioxane (500 μL) and 6 M HCl in H₂O (1 mL) was added. The reaction mixture was shaken at 100° C. for 4 h and the solvent was evaporated to give a dark residue which was suspended in DCE:MeOH 85:15 and then passed through a silica gel plug. The solvent was evaporated and the resulting material was purified by preparative LC-MS. MS m/z 331 [M+H]⁺

The following examples in the table were prepared essentially as described above.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Salt Starting material 817 N-(1,2,3,4,4a,9a- 331 racemic TFA benzenesulfonyl chloride hexahydro[1]benzofuro[2,3- c]pyridin-6-yl)benzenesulfonamide 818 6-chloro-N-(1,2,3,4,4a,9a- 411 Racemic HCl 6-chloroimidazo[2,1- hexahydro[1]benzofuro[2,3- b][1,3]thiazole-5-sulfonyl c]pyridin-6-yl)imidazo[2,1- chloride b][1,3]thiazole-5-sulfonamide 819 N-(1,2,3,4,4a,9a- 381 Racemic TFA naphthalene-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)naphthalene-2- sulfonamide 820 N-(1,2,3,4,4a,9a- 359 Racemic TFA 2,5- hexahydro[1]benzofuro[2,3- dimethylbenzenesulfonyl c]pyridin-6-yl)-2,5- chloride dimethylbenzenesulfonamide 821 N-(1,2,3,4,4a,9a- 361 racemic TFA 4- hexahydro[1]benzofuro[2,3- methoxybenzenesulfonyl c]pyridin-6-yl)-4- chloride methoxybenzenesulfonamide 822 N-(1,2,3,4,4a,9a- 361 racemic TFA 3- hexahydro[1]benzofuro[2,3- methoxybenzenesulfonyl c]pyridin-6-yl)-3- chloride methoxybenzenesulfonamide 823 4-chloro-N-(1,2,3,4,4a,9a- 365 racemic TFA 4-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)benzenesulfonamide 824 N-(1,2,3,4,4a,9a- 373 racemic TFA 4-(propan-2- hexahydro[1]benzofuro[2,3- yl)benzenesulfonyl c]pyridin-6-yl)-4-(propan-2- chloride yl)benzenesulfonamide 825 N-(1,2,3,4,4a,9a- 381 racemic TFA naphthalene-1-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)naphthalene-1- sulfonamide 826 3-chloro-N-(1,2,3,4,4a,9a- 365 racemic TFA 3-chlorobenzenesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)benzenesulfonamide 827 3,4-dichloro-N-(1,2,3,4,4a,9a- 399 racemic TFA 3,4- hexahydro[1]benzofuro[2,3- dichlorobenzenesulfonyl c]pyridin-6-yl)benzenesulfonamide chloride 828 3,5-dichloro-N-(1,2,3,4,4a,9a- 399 racemic TFA 3,5- hexahydro[1]benzofuro[2,3- dichlorobenzenesulfonyl c]pyridin-6-yl)benzenesulfonamide chloride 829 2,3-dichloro-N-(1,2,3,4,4a,9a- 399 racemic TFA 2,3- hexahydro[1]benzofuro[2,3- dichlorobenzenesulfonyl c]pyridin-6-yl)benzenesulfonamide chloride 830 5-chloro-N-(1,2,3,4,4a,9a- 435 racemic TFA 5-chloro-3-methyl-1- hexahydro[1]benzofuro[2,3- benzothiophene-2- c]pyridin-6-yl)-3-methyl-1- sulfonyl chloride benzothiophene-2-sulfonamide 831 N-(1,2,3,4,4a,9a- 345 racemic TFA phenylmethanesulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)-1- phenylmethanesulfonamide 832 N-(1,2,3,4,4a,9a- 297 racemic TFA propane-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)propane-2- sulfonamide 833 N-(1,2,3,4,4a,9a- 371 racemic TFA 1-benzofuran-2-sulfonyl hexahydro[1]benzofuro[2,3- chloride c]pyridin-6-yl)-1-benzofuran-2- sulfonamide 834 N-(1,2,3,4,4a,9a- 387 racemic TFA 1-benzothiophene-2- hexahydro[1]benzofuro[2,3- sulfonyl chloride c]pyridin-6-yl)-1-benzothiophene- 2-sulfonamide

Example 835 6-Chloro-N-[1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-7-yl]-N-methylimidazo[2,1-b][1,3]thiazole-5-sulfonamide

Step 1 7-Methylamino-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Anhydrous DMF was sparged with argon gas for 1 h before being used. Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (1 g, 2.5 mmol) sodium tert-butoxide (723 mg, 7.5 mmol), neocuproine (52 mg, 0.25 mmol) and copper (I) iodide (290 mg, 1.5 mmol) were dissolved in anhydrous DMF (20 mL). To this mixture was added a 2M solution of methylamine in THF (6 mL) and the reaction shaken at 80° C. for 16 h. The solvent was evaporated and the residue dissolved in DCM and washed with H₂O (3×). The solvent was evaporated and the crude residue used as such in the next reaction step.

Step 2

Crude N-methyl aniline (200 mg, 0.8 mmol) was dissolved in DCE (7 mL) and DIEA (210 μL, 1.2 mmol) was added followed by 6-chloro-N-[1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-7-yl]-N-methylimidazo[2,1-b][1,3]thiazole-5-sulfonamide (217 mg, 0.84 mmol). The reaction mixture was shaken for 1 h and TFA (7 mL) was added. After shaking for 30 min the solvent was evaporated and the residue purified by preparative LC-MS. The product was converted to the HCl salt by dissolving the product in DCM, adding 2M HCl in Et₂O and evaporating the solvent. MS m/z 425 [M+H]⁺

Example 836 N-(4-Chlorophenyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine-6-sulfonamide

Step 1 2-Acetyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine-6-sulfonyl chloride

To a solution of 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (825 mg, 3.8 mmol) and thionyl chloride at 0° C., was added dropwise chlorosulfonic acid (1.25 g). The reaction mixture was stirred for 5 min at 0° C., for 2 h at r.t. and poured tehn into ice/H₂O (75 g). The solution was brought to pH 7 by adding sodium carbonate and extracted with 75 mL ethyl acetate (2×). The combined organic layers were washed with H₂O (2×), separated, and the solvent was evaporated. The resulting sulfonyl chloride was used in the next reaction step without further purification.

Step 2 N-(4-Chlorophenyl)-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine-6-sulfonamide

A 0.4 M solution of 2-acetyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine-6-sulfonyl chloride (6.8 g) in DMF (54 mL) was prepared. To 1.5 mL of the 0.4 M solution of sulfonylchloride prepared above, was added DIEA (112 μL) followed by 4-chloro-penylamine (84 mg). The reaction mixture was shaken for 16 h and the solvent was evaporated. The crude product was dissolved in dioxane (500 μL) and 6 M HCl in H₂O (1 mL) was added. The reaction mixture was shaken at 100° C. for 4 h, the solvent was then evaporated. The resulting dark residue was suspended in DCE:MeOH 85:15 and passed through a silica gel plug. The eluate was evaporated and the resulting product purified by preparative LC-MS. MS m/z 365 [M+H]⁺

The following examples were prepared essentially as described above. All compounds were isolated as HCl salts.

MS m/z Ex. # Name [M + H]⁺ Stereochemistry Starting material 836 N-(4-chlorophenyl)-1,2,3,4,4a,9a- 365 racemic 4-chloroaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 837 N-(naphthalen-1-yl)-1,2,3,4,4a,9a- 381 racemic naphthalen-1-amine hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 838 6-(2,3-dihydro-1H-indol-1- 357 racemic 2,3-dihydro-1H-indole ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 839 N-(2-fluorophenyl)-1,2,3,4,4a,9a- 349 racemic 2-fluoroaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 840 N-(2-chlorophenyl)-1,2,3,4,4a,9a- 365 racemic 2-chloroaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 841 N-(2-methoxyphenyl)-1,2,3,4,4a,9a- 361 racemic 2-methoxyaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 842 N-(2,3-difluorophenyl)- 367 racemic 2,3-difluoroaniline 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 843 N-(3,5-dichlorophenyl)- 399 racemic 3,5-dichloroaniline 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 844 N-(2,4-dichlorophenyl)- 399 racemic 2,4-dichloroaniline 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 845 6-[(4-phenylpiperazin-1-yl)sulfonyl]- 400 racemic 1-phenylpiperazine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 846 N-(3-fluorophenyl)-1,2,3,4,4a,9a- 349 racemic 3-fluoroaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 847 N-(4-fluorophenyl)-1,2,3,4,4a,9a- 349 racemic 4-fluoroaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 848 N-phenyl-1,2,3,4,4a,9a- 331 racemic aniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 849 N-cyclohexy1-1,2,3,4,4a,9a- 337 racemic cyclohexanamine hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 850 N-(3-methoxyphenyl)-1,2,3,4,4a,9a- 361 racemic 3-methoxyaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 851 N-(3-fluoro-4-methylphenyl)- 363 racemic 3-fluoro-4-methylaniline 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 852 N-(3,4-dichlorophenyl)- 399 racemic 3,4-dichloroaniline 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 853 N-(3-chlorophenyl)-1,2,3,4,4a,9a- 365 racemic 3-chloroaniline hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 854 N-(4-chlorobenzyl)-1,2,3,4,4a,9a- 379 racemic 1-(4- hexahydro[1]benzofuro[2,3- chlorophenyl)methanamine c]pyridine-6-sulfonamide 855 N-(2-phenylethyl)-1,2,3,4,4a,9a- 359 racemic 2-phenylethanamine hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 856 6-(3,4-dihydroisoquinolin-2(1H)- 371 racemic 1,2,3,4- ylsulfonyl)-1,2,3,4,4a,9a- tetrahydroisoquinoline hexahydro[1]benzofuro[2,3- c]pyridine 857 N-(2,3-dihydro-1H-inden-2-yl)- 371 racemic 2,3-dihydro-1H-inden-2- 1,2,3,4,4a,9a- amine hexahydro[1]benzofuro[2,3- c]pyridine-6-sulfonamide 858 N-benzyl-N-methyl-1,2,3,4,4a,9a- 359 racemic N-methyl-1- hexahydro[1]benzofuro[2,3- phenylmethanamine c]pyridine-6-sulfonamide 859 6-[(6,7-dimethoxy-3,4- 431 racemic 6,7-dimethoxy-1,2,3,4- dihydroisoquinolin-2(1H)- tetrahydroisoquinoline yl)sulfonyl]-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 860 6-(octahydroisoquinolin-2(1H)- 377 racemic decahydroisoquinoline ylsulfonyl)-1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 861 6-[(4-phenylpiperidin-1-yl)sulfonyl]- 399 racemic 4-phenylpiperidine 1,2,3,4,4a,9a- hexahydro[1]benzofuro[2,3- c]pyridine 862 1′-(1,2,3,4,4a,9a- 427 racemic 3H-spiro[2-benzofuran- hexahydro[1]benzofuro[2,3- 1,4′-piperidine] c]pyridin-6-ylsulfonyl)-3H-spiro[2- benzofuran-1,4′-piperidine]

NMR data for a select number of Examples is provided below:

Ex. No. Name ¹H-NMR Data (400 MHz) 30 7-[(3-fluorophenyl)sulfonyl]-3,4,4′,5′- (CDCl₃): δ 8.08 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), tetrahydro-2H-spiro[1-benzofuro[2,3- 7.77 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), c]pyridine-1,3′-furan] 7.56 (d, J = 8.2 Hz, 1H), 7.49 (m, 1H), 7.25 (m, 1H), 4.19 (m, 1H), 4.13 (m, 1H), 3.97 (m, 2H), 3.24 (m, 1H), 3.17 (m, 1H), 2.74 (m, 1H), 2.58 (m, 1H), 2.10 (m, 1H) 34 1-(difluoromethyl)-1-methyl-7-{[3- (DMSO-d₆): δ 8.34 (s, 1H), 7.92 (m, 2H), 7.50 (m, (propan-2-yloxy)phenyl]sulfonyl}- 2H), 7.44 (d, J = 1.8 Hz, 1H), 7.20 (m, 1H), 6.58 (t, 1,2,3,4-tetrahydro[1]benzofuro[2,3- J = 52.6 Hz, 1H), 4.73 (m, 1H), 3.43 (m, 2H), c]pyridine 2.93 (m, 2H), 1.70 (br.s, 3H), 1.26 (d, J = 6.0 Hz, 6H) 35 1,1-bis(fluoromethyl)-7-[(3- (CDCl₃): δ 8.12 (s, 1H), 7.85 (dd, J = 1.4, 8.3 Hz, fluorophenyl)sulfonyl]-1,2,3,4- 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), tetrahydro[1]benzofuro[2,3-c]pyridine 7.62 (d, J = 8.2 Hz, 1H), 7.50 (m, 1H), 7.25 (m, 1H), 4.70 (m, 4H), 3.26 (t, J = 5.5 Hz, 2H), 2.75 (t, J = 5.5 Hz) 37 7-[(3-fluorophenyl)sulfonyl]-1-methyl- (DMSO-d₆): δ 8.36 (s, 1H), 7.91 (m, 2H), 7.86 (m, 1-(trifluoromethyl)-1,2,3,4- 2H), 7.67 (m, 1H), 7.55 (m, 1H), 3.13 (m, 1H), tetrahydro[1]benzofuro[2,3-c]pyridine 3.08 (m, 1H), 2.72 (m, 2H), 1.59 (s, 3H) 40 2-{7-[(3-fluorophenyl)sulfonyl]-1- (DMSO-d₆): δ 9.90 (br.s, 1H), 9.58 (br.s, 1H), methyl 1,2,3,4- 8.30 (d, J = 1.3 Hz, 1H), 7.90 (m, 4H), 7.67 (m, 1H), tetrahydro[1]benzofuro[2,3-c]pyridin- 7.56 (m, 1H), 3.57 (s, 2H), 3.56 (m, 1H), 3.26 (m, 1H), 1-yl}-N,N-dimethylacetamide 3.01 (s, 3H), 2.96 (m, 2H), 2.84 (s, 3H), 1.78 (s, 3H) 50 2-{7-[(3-fluorophenyl)sulfonyl]-1- (DMSO-d₆): δ 9.80 (br, m, 2 H), 8.26 (s, 1H), methyl-1,2,3,4- 7.90 (m, 4H), 7.67 (q, J = 6.1 Hz, 1H), 7.55 (t, J = 8.1 Hz, tetrahydro[1]benzofuro[2,3-c]pyridin- 1H), 3.55 (m, 2H), 3.32 (s, 2H), 3.24 (m, 1H), 1-yl}-N,N-dimethylacetamide 3.01 (s, 3H), 2.95 (m, 1H), 2.84 (s, 3H), 1.76 (s, 3H) 56 7-[(3-fluorophenyl)sulfonyl]-2′-methyl- (CDCl₃): δ 8.08 (s, 1H), 7.83 (d J = 8.1 Hz, 1H), 3,4,4′,5′-tetrahydro-2H-spiro[1- 7.78 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.58 (d, benzofuro[2,3-c]pyridine-1,3′-furan] J = 8.2 Hz, 1H), 7.49 (m, 1H), 7.25 (m, 1H), 4.23 (m, 1H), 4.03 (m, 2H), 3.17 (m, 2H), 2.72 (m, 2H), 2.64 (m, 1H), 2.04 (m, 1H), 1.77 (br.s, 1H), 1.13 (d, J = 6.3 Hz) 57 7-[(3-fluorophenyl)sulfonyl]-2′-methyl- (CDCl₃): δ 8.07 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 3,4,4′,5′-tetrahydro-2H-spiro[1- 7.77 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), benzofuro[2,3-c]pyridine-1,3′-furan] 7.56 (d, J = 8.1 Hz, 1H), 7.49 (m, 1H), 7.25 (m, 1H), 4.35 (m, 1H), 4.14 (m, 1H), 4.05 (m, 1H), 3.28 (m, 1H), 3.10 (m, 1H), 2.70 (m, 2H), 2.49 (m, 1H), 2.19 (m, 1H), 1.21 (d, J = 6.2 Hz, 3H) 58 7-[(3-fluorophenyl)sulfonyl]-2′-methyl- (DMSO-d₆): δ 10.39 (br.s, 2H), 8.36 (s, 1H), 3,4,4′,5′-tetrahydro-2H-spiro[1- 7.90 (m, 3H), 7.87 (d, J = 7.7 Hz, 1H), 7.67 (m, 1H), benzofuro[2,3-c]pyridine-1,3′-furan] 7.56 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H), 3.50 (m, 2H), 3.00 (m, 2H), 2.64 (m, 1H), 2.56 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H) 59 7-[(3-fluorophenyl)sulfonyl]-2′-methyl- (DMSO-d₆): δ 10.39 (br.s, 2H), 8.36 (s, 1H), 3,4,4′,5′-tetrahydro-2H-spiro[1- 7.90 (m, 3H), 7.87 (d, J = 7.7 Hz, 1H), 7.67 (m, 1H), benzofuro[2,3-c]pyridine-1,3′-furan] 7.56 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H), 3.50 (m, 2H), 3.00 (m, 2H), 2.64 (m, 1H), 2.56 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H) 60 7-[(3-fluorophenyl)sulfonyl]-2′-methyl- (DMSO-d₆): δ 10.50 (br.s, 1H), 9.55 br.s, 1H), 3,4,4′,5′-tetrahydro-2H-spiro[1- 8.33 (s, 1H), 7.89 (m, 4H), 7.66 (m, 1H), 7.55 (m, 1H), benzofuro[2,3-c]pyridine-1,3′-furan] 4.35 (m, 1H), 4.11 (m, 1H), 3.95 (m, 1H), 3.48 (m, 2H), 3.02 (m, 2H), 2.59 (m, 2H), 1.29 (d, J = 6.0 Hz, 3H) 61 7-[(3-fluorophenyl)sulfonyl]-2′-methyl- (DMSO-d₆): δ 10.50 (br.s, 1H), 9.55 (br.s, 1H), 3,4,4′,5′-tetrahydro-2H-spiro[1- 8.33 (s, 1H), 7.89 (m, 4H), 7.66 (m, 1H), 7.55 (m, 1H), benzofuro[2,3-c]pyridine-1,3′-furan] 4.35 (m, 1H), 4.11 (m, 1H), 3.95 (m, 1H), 3.48 (m, 2H), 3.02 (m, 2H), 2.59 (m, 2H), 1.29 (d, J = 6.0 Hz, 3H) 63 7-({3-[(6-methylpyrazin-2- (DMSO-d₆): δ 1.49-1.65 (m, 2H), 2.08-2.16 (m, 2H), yl)oxy]phenyl}sulfonyl)-1,2,3,4,4a,9a- 2.95 (s, 3H), 3.53-3.60 (m, 2H), 4.91-4.98 (m, 2H), hexahydro[1]benzofuro[2,3-c]pyridine 7.04 (d, J = 4.1 Hz, 1H), 7.24-7.58 (m, 7H), 8.78 (s, 1H), 9.59 (s, 1H), 10.36 (br s, 1H) 64 7-[(2,6-dichlorophenyl)sulfonyl]- (DMSO-d₆): δ 2.15 (s, 2H), 3.44 (s, 2H), 4.96 (s, 1,2,3,4,4a,9a- 2H), 7.32 (s, 1H), 7.52-7.75 (m, 5H), 8.78 (s, 1H), hexahydro[1]benzofuro[2,3-c]pyridine 9.52 (s, 1H) 65 7-(1,3-benzothiazol-2-ylsulfonyl)- (DMSO-d₆): δ 1.49-1.62 (m, 1H), 2.11-2.20 (m, 1H), 1,2,3,4,4a,9a- 2.98 (s, 2H), 3.42 (s, 2H), 3.58-3.66 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridine 5.00 (s, 1H), 7.51 (s, 1H), 7.58-7.72 (m, 4H), 8.24 (dd, J = 11.8, 4.0, 2H), 7.78 (br s, 1H), 9.43 (br s, 1H) 66 7-[(3-chloro-2-methylphenyl)sulfonyl]- (DMSO-d₆): δ 1.47-1.60 (m, 1H), 2.10-2.20 (m, 1H), 1,2,3,4,4a,9a- 2.42 (s, 3H), 2.89-3.02 (m, 2H), 3.47-3.68 (m, 3H), hexahydro[1]benzofuro[2,3-c]pyridine 4.94-5.00 (m, 1H), 7.26 (s, 1H), 7.41-7.61 (m, 3H), 7.80-7.87 (m, 1H), 8.10-8.17 (m, 1H), 8.72 (br s, 1H), 9.31 (br s, 1H) 67 7-(2,1,3-benzothiadiazol-4-ylsulfonyl)- (DMSO-d₆): δ 1.43-1.59 (m, 1H), 2.04-2.15 (m, 1H), 1,2,3,4,4a,9a- 2.86-3.01 (m, 2H), 3.38-3.46 (m, 1H), 3.48-3.63 (m, hexahydro[1]benzofuro[2,3-c]pyridine 2H), 4.87-4.93 (m, 1H), 7.50-7.63 (m, 2H), 7.70-7.76 (m, 1H), 7.92-8.00 (m, 1H), 8.43-8.56 (m, 2H), 8.77 (br s, 1H), 9.43 (br s, 1H) 68 7-[(1-methyl-1H-indol-4-yl)sulfonyl]- (DMSO-d₆): δ 1.37-1.52 (m, 1H), 2.02-2.13 (m, 1H), 1,2,3,4,4a,9a- 2.84-2.99 (m, 2H), 3.40-3.62 (m, 3H), 3.82 (s, 3H), hexahydro[1]benzofuro[2,3-c]pyridine 4.83-4.94 (m, 1H), 6.70 (s, 1H), 7.38-7.48 (m, 2H), 7.45 (d, J = 4.0 Hz, 1H), 7.53-7.62 (m, 2H), 7.76-7.82 (m, 2H), 8.78 (br s, 1H), 9.35 (br s, 1H) 69 7-(1H-benzimidazol-2-ylsulfonyl)- (DMSO-d₆): δ 1.51-1.62 (m, 1H), 2.08-2.20 (m, 1H), 1,2,3,4,4a,9a- 2.88-2.99 (m, 2H), 3.36-3.47 (m, 1H), 3.51-3.65 (m, hexahydro[1]benzofuro[2,3-c]pyridine 2H), 4.96-5.01 (m, 1H), 7.32-7.40 (m, 2H), 7.46 (s, 1H), 7.60-7.77 (m, 5H), 8.73-8.85 (m, 1H), 9.52-9.62 (m, 1H) 70 7-[(5-methyl-2,1,3-benzothiadiazol-4- (DMSO-d₆): δ 1.68-1.80 (m, 1H), 2.01-2.12 (m, 1H), yl)sulfonyl]-1,2,3,4,4a,9a- 2.99 (s, 3H), 3.05-3.21 (m, 3H), 3.66-3.74 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridine 3.80-3.93 (m, 1H), 4.92-5.08 (m, 1H), 7.28-7.45 (m, 3H), 7.58-7.82 (m, 2H), 8.23-8.31 (m, 1H) 71 7-[(5-methoxy-1,3-benzothiazol-2- (DMSO-d₆): δ 1.72-1.86 (m, 1H), 2.04-2.13 (m, 1H), yl)sulfonyl]-1,2,3,4,4a,9a- 2.85-3.02 (m, 1H), 3.05-3.18 (m, 1H), 3.30-3.48 (m, hexahydro[1]benzofuro[2,3-c]pyridine 1H), 3.60-3.96 (m, 2H), 3.86 (s, 3H), 5.00-5.16 (m, 1H), 7.22-7.32 (m, 2H), 7.52-7.62 (m, 4H), 7.73 (s, 1H), 8.15 (m, 1H) 72 7-(2,1,3-benzoxadiazol-4-ylsulfonyl)- (DMSO-d₆): δ 1.72-1.84 (m, 1H), 2.01-2.12 (m, 1H), 1,2,3,4,4a,9a- 2.83-3.02 (m, 1H), 3.03-3.15 (m, 1H), 3.33-3.46 (m, hexahydro[1]benzofuro[2,3-c]pyridine 1H), 3.69-3.78 (m, 1H), 3.82-3.94 (m, 1H), 4.98-5.12 (m, 1H), 7.36 (s, 1H), 7.50-7.57 (m, 1H), 7.62-7.69 (m, 1H), 7.78-7.85 (m, 1H), 8.33-8.48 (m, 2H) 73 N-[3-(1,2,3,4,4a,9a- DMSO-d₆): δ 1.48-1.58 (m, 1H), 2.04 (s, 3H), hexahydro[1]benzofuro[2,3-c]pyridin- 2.04-2.18 (m, 1H), 2.84-2.99 (m, 2H), 3.38-3.44 (m, 1H), 7-ylsulfonyl)phenyl]acetamide 3.49-3.60 (m, 1H), 4.91-4.98 (m, 1H), 7.32 (s, 1H), 7.44-7.62 (m, 4H), 7.76-7.81 (m, 1H), 8.30 (s, 1H), 8.81 (br s, 1H), 9.61 (br s, 1H), 10.49 (s, 1H) 79 (4aR,9aS)-7-{[3-methoxy-5-(propan- (DMSO-d₆): δ 1.23 (d, J = 3.4, 6H), 1.47-1.60 (m, 2-yloxy)phenyl]sulfonyl}- 1H), 2.10-2.18 (m, 1H), 2.88-2.99 (m, 2H), 1,2,3,4,4a,9a- 3.38-3.46 (m, 1H), 3.49-3.59 (m, 2H), 3.80 (s, 3H), hexahydro[1]benzofuro[2,3-c]pyridine 4.68-4.76 (m, 1H), 4.95 (s, 1H), 6.74 (s, 1H), 6.92-7.02 (m, 2H), 7.45 (s, 1H), 7.50-7.62 (m, 2H), 9.21 (br s, 2H) 80 7-[(5-chloro-2- (DMSO-d₆): δ 2.96 (s, 2H), 3.42 (s, 2H), 3.72 (s, methoxyphenyl)sulfonyl]-1,2,3,4- 3H), 4.48 (s, 2H), 7.18 (d, J = 4.4 Hz, 1H), tetrahydro[1]benzofuro[2,3-c]pyridine 7.70-7.78 (m, 1H), 7.88 (s, 2H), 7.99 (s, 1H), 8.22 (s, 1H), 9.80 (s, 2H) 81 7-[(3-chloro-2-fluorophenyl)sulfonyl]- (DMSO-d₆): δ 2.98 (s, 2H), 3.42 (s, 2H), 4.46 (s, 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2H), 7.52 (t, J = 4.2 Hz, 1H), 7.85-8.09 (m, 4H), c]pyridine 8.24 (s, 1H), 10.18 (s, 2H) 82 7-[(3-chloro-2-methylphenyl)sulfonyl]- (DMSO-d₆): δ 2.46 (s, 3H), 2.94 (s, 2H), 3.52 (s, 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2H), 4.47 (s, 2H), 7.44-7.60 (m, 1H), 7.66-7.93 (m, c]pyridine 3H), 8.08-8.28 (m, 2H), 9.90 (s, 2H) 88 6-[(2,3-dichlorophenyl)sulfonyl]-7- (DMSO-d₆): δ 1.44-1.60 (m, 1H), 2.06-2.18 (m, 1H), methoxy-1,2,3,4,4a,9a- 2.55 (s, 3H), 2.88-3.02 (m, 2H), 3.37-3.47 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridine 3.51-3.62 (m, 2H), 4.91-4.99 (m, 1H), 7.38 (s, 1H), 7.56-7.64 (m, 2H), 8.08 (s, 1H), 8.15 (d, J = 3.5 Hz, 1H), 8.71 (br s, 1H), 9.23 (br s, 1H) 472 1-(difluoromethyl)-7-[(2,3- (DMSO-d₆): δ 8.28 (s, 1H), 7.96 (m, 3H), 7.84 (m, difluorophenyl)sulfonyl]-1-methyl- 1H), 7.53 (M, 1H), 6.62 (t, J = 52.2 Hz, 1H), 1,2,3,4-tetrahydro[1]benzofuro[2,3- 3.57 (br.s, 2H), 3.46 (m, 2H), 2.98 (m, 2H), 1.72 (s, 3H) c]pyridine 473 7-[(2,3-difluorophenyl)sulfonyl]- (CDCl₃): δ 10.23 (br.s, 1H), 8.26 (s, 1H), 7.94 (m, 3,4,4′,5′-tetrahydro-2H-spiro[1- 3H), 7.84 (d, J = 8.9 Hz, 1H), 7.53 (m, 1H), 4.27 (d, benzofuro[2,3-c]pyridine-1,3′-furan] J = 10.1 Hz, 1H), 4.15 (d, J = 7.9 Hz, 1H), 4.03 (m, 2H), 3.52 (m, 2H), 3.38 (m, 2H), 3.01 (m, 2H), 2.58 (m, 1H) 476 2-fluoro-6-(1,2,3,4,4a,9a- (DMSO-d₆): δ 8.82 (br.s, 1H), 7.96 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridin- 7.70 (m, 2H), 7.57 (m, 2H), 7.48 (m, 1H), 4.93 (m, 1H), 7-ylsulfonyl)-N,N-dimethylbenzamide 3.57 (m, 2H), 3.44 (m, 1H), 3.40 (m, 1H), 3.04 (s, 3H), 2.97 (m, 2H), 2.77 (m, 3H), 2.13 (m, 1H), 1.51 (m, 1H) 477 2-fluoro-6-(1,2,3,4,4a,9a- (DMSO-d₆): δ 8.95 (br.s, 1H), 8.62 (d, J = 4.8 Hz, hexahydro[1]benzofuro[2,3-c]pyridin- 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.67 (m, 2H), 7.60 (d, 7-ylsulfonyl)-N-methylbenzamide J = 9.3 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.51 (s, 1H), 4.94 (m, 1H), 3.56 (m, 1H), 3.43 (m, 1H), 2.96 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H), 2.12 (m, 1H), 1.51 (m, 1H) 478 N-methyl-3-(1,2,3,4- (DMSO-d₆): δ 9.66 (br.s, 2H), 8.75 (m, 1H), 8.41 (s, tetrahydro[1]benzofuro[2,3-c]pyridin- 1H), 8.33 (s, 1H), 8.11 (m, 2H), 7.91 (d, J = 8.3 Hz, 7-ylsulfonyl)benzamide 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 4.48 (m, 2H), 3.45 (m, 2H), 2.94 (m, 2H), 2.80 (d, J = 4.6 Hz, 3H) 479 2-fluoro-N,N-dimethyl-6-(1,2,3,4- (DMSO-d₆): δ 9.45 (m, 2H), 8.26 (s, 1H), 8.02 (d, tetrahydro[1]benzofuro[2,3-c]pyridin- J = 7.2 Hz, 1H), 7.92 (d, J = 9.9 Hz, 1H), 7.86 (d, J = 8.3 Hz, 7-ylsulfonyl)benzamide 1H), 7.71 (m, 2H), 4.50 (m, 2H), 3.47 (m, 2H), 3.06 (s, 3H), 2.95 (m, 2H), 2.79 (s, 3H) 549 7-{[3-(prop-2-yn-1- (DMSO-d₆): δ 1.47-1.58 (m, 1H), 2.05-2.17 (m, 1H), yloxy)phenyl]sulfonyl}-1,2,3,4,4a,9a- 2.90-2.97 (m, 2H), 2.35-2.42 (m, 1H), 2.51-2.62 (m, hexahydro[1]benzofuro[2,3-c]pyridine 3H), 4.90-4.96 (m, 3H), 7.23-7.29 (m, 1H), 7.42-7.59 (m, 6H), 9.05 (br s, 2H) 550 2-{[3-(1,2,3,4,4a,9a- (DMSO-d₆): δ 1.71-1.82 (m, 1H), 2.02-2.14 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridin- 2.91-3.02 (m, 1H), 3.08-3.20 (m, 1H), 3.31-3.44 (m, 7- 1H), 3.63-3.71 (m, 1H), 3.67-3.73 (m, 1H), ylsulfonyl)phenoxy]methyl}benzonitrile 3.84-3.90 (m, 1H), 5.34 (s, 2H), 7.25 (s, 1H), 7.31-7.36 (m, 1H), 7.40-7.61 (m, 6H), 7.78-7.83 (m, 2H), 7.89-7.94 (m, 1H) 551 4-{[3-(1,2,3,4,4a,9a- (DMSO-d₆): δ 1.71-1.79 (m, 1H), 2.03-2.14 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridin- 2.88-3.00 (m, 1H), 3.05-3.20 (m, 1H), 3.32-3.43 (m, 7- 1H), 3.68-3.75 (m, 1H), 3.82-3.90 (m, 1H), ylsulfonyl)phenoxy]methyl}benzonitrile 4.99-5.10 (m, 1H), 5.32 (s, 2H), 7.21 (s, 1H), 7.38-7.43 (m, 2H), 7.48-7.55 (m, 4H), 7.61-7.68 (m, 2H), 7.82-7.89 (m, 2H) 552 3-{[3-(1,2,3,4,4a,9a- (DMSO-d₆): δ 1.71-1.79 (m, 1H), 2.03-2.13 (m, 1H), hexahydro[1]benzofuro[2,3-c]pyridin- 2.88-3.02 (m, 1H), 3.05-3.21 (m, 1H), 3.32-3.46 (m, 7- 1H), 3.64-3.74 (m, 1H), 3.86-3.92 (m, 1H), ylsulfonyl)phenoxy]methyl}benzonitrile 4.97-5.10 (m, 1H), 5.27 (s, 2H), 7.26 (s, 1H), 7.30-7.36 (m, 1H), 7.42-7.66 (m, 6H), 7.79-7.86 (m, 2H), 7.92 (s, 1H) 581 7-{[3-(tetrahydro-2H-pyran-4- (DMSO-d₆): δ 1.28-1.38 (m, 2H), 1.46-1.58 (m, 1H), ylmethoxy)phenyl]sulfonyl}- 1.61-1.69 (m, 2H), 1.92-2.04 (m, 1H), 2.08-2.15 (m, 1,2,3,4,4a,9a- 1H), 2.90-2.97 (m, 2H), 3.33-3.42 (m, 3H), hexahydro[1]benzofuro[2,3-c]pyridine 3.50-3.58 (m, 2H), 3.82-3.91 (m, 4H), 4.89-4.95 (m, 1H), 7.22-7.25 (m, 1H), 7.42 (s, 2H), 7.47-7.58 (m, 4H), 8.78 (br s, 1H), 9.33 (br s, 1H)

Preparations P01 Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1 Tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

A solution of DEAD (147 g, 0.34 mol) in toluene (40 wt %) was added over 45 min to a solution of N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine (48 g, 0.24 mol) and 2-Bromo-5-methoxyphenol (49 g, 0.24 mol) in THF (800 mL). The reaction mixture was kept under 35° C. using a water bath cooling. After 1 h stirring, the solvent was evaporated, the residue suspended in 500 mL ethyl acetate:heptane (20:80) and filtered off. The combined filtrates were washed with 500 mL of 0.6N NaOH and twice with 500 mL (H₂O) and concentated. Silica gel (600 g) purification eluting with ethyl acetate:heptane afforded 73 g of the bromo ether.

The bromo ether (73 g) was dissolved in toluene (3.5 L), tributyltin hydride (82 g, 0.28 mol) was added followed by AIBN (3 g, 0.02 mol). The reaction mixture was stirred at 80° C. for 5 h and DBU (48 g, 0.32 mol) was added at r.t. Methyl t-Butyl ether (1.5 L) was added, the suspension passed through silica gel and the solvent was evaporated. Crystallization using heptane (150 mL) and drying under h.v. afforded 33.8 g of tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate.

Step 2 Tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (P02)

Boron tribromide (285 mL, 1 M, 0.285 mol) in DCM was added over 45 min to a solution of tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (33.3 g, 0.11 mol) in DCM (1.2 L). The reaction mixture was kept at 5-8° C. using a water bath cooling. After 1 h stirring, H₂O (250 mL) and NaOH (350 mL, 3 M) were added, followed by di-tert-butyl dicarbonate (59.6 g, 0.27 mol). After 16 h stirring, the layers were separated, the organic layer was washed with 0.3 N HCl and H₂O, and concentrated. Crystallization using heptane and drying under house vacuum (h.v.) afforded 74 g of expected product. MS m/z 292 [M+H]⁺

Step 3 Tert-butyl 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

A solution of triflic anhydride (59 g) in DCM (0.2 L) was added over 30 min to a cold solution of tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (55.4 g, 0.19 mol), DMAP (11.6 g, 0.09 mol) and triethylamine (38.5 g, 0.38 mol) DCM (1.1 L). The reaction mixture was kept at 3-6° C. using a water bath cooling. After 30 min stirring, H₂O (250 mL) was added, the layers were separated, the organic layer was washed twice with 0.5 N HCl, and once with H₂O. Magnesium sulfate and DARCO G-60 were added. Filtration of the solid followed by evaporation and drying under h.v. afforded 74 g of the desired triflate.

A solution of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium II in DCM (4.7 g, 0.17 mol), [1,1′-bis(diphenyl-phosphino)ferrocene] and pinacolboran (32.8 g, 0.25 mol) were added to a solution of the triflate (74 g, 0.17 mol) in absolute dioxane. Triethylamine was added, the reaction mixture was heated at 98° C. for 3 h and the solvent was evaporated. The residue was dissolved in DCM (1.5 L), washed twice with H₂O, once with 5% citric acid solution, diluted with ACN and passed through a silica gel plug. The solution was concentrated and cooled down to −20° C., the precipitate was collected, dried under h.v. to afford 42 g of the 7-pinacoloboronate. MS m/z 420 [M+H]⁺

Step 4 Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Tert-butyl 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (20 g, 0.05 mol) was dissolved in THF (0.4 L) and a solution of Chloramine T (28.1 g, 0.1 mol) in H₂O (0.2 L) was added, followed by a solution of sodium iodide (15 g, 0.1 mol) in H₂O (0.2 L) over 20 min. After 20 h stirring, of chloramine T (2.8 g, 0.01 mol) and sodium iodide (1.5 g, 0.01 mol) were added. The reaction mixture was stirred for 20 h, the solvent was evaporated, ethyl acetate and H₂O were added. The layers were separated, and the organic layer was washed with H₂O.

Silica gel (300 g) purification eluting with ethyl acetate:heptane (20:80) afforded 18 g of the crude product. Crystallization using acetonitrile and drying under h.v. afforded 16 g of the title compound (P01). MS m/z 402 [M+H]⁺

Enantiomers of tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01

Separation by SFC of tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01 on a Chiralpak AD-H column (21×250 cm) at 35° C. and eluting with 30% MeOH: 0.1% diethylamine (flow: 16 mL/min) and CO₂ (36 mL/min) yielded enantiomer 1 P03 and enantiomer 2 P04 of tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate.

P05 Tert-butyl 6-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Tert-butyl 6-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01 starting from N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromo-4-methoxyphenol. MS m/z 402 [M+H]⁺

P06 Tert-butyl 6-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Tert-butyl 6-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromo-4-methoxyphenol.

P07 Tert-butyl 8-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1 Tert-butyl 8-bromo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Prepared as described for tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2,6-dibromo-phenol.

Step 2 8-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Anhydrous DMA (80 mL) was degassed by sparging with argon gas. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)/DCM complex (1:1) (340 mg, 0.42 mmol), 1,1′-bis(diphenylphosphino)ferrocene (235 mg, 0.423 mmol), Potassium acetate (4.15 g, 42.3 mmol) and 5,5,5′,5-Tetramethyl-2,2′-bi[1,3,2-dioxaborinanyl] (3.19 g, 14.1 mmol) were suspended in anhydrous DMA (20 mL, 200 mmol). To this suspension a solution of 8-bromo-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (5.00 g, 14.1 mmol) in anhydrous DMA (60 mL, 600 mmol) was added via a canula. The reaction was stirred at 80° C. overnight under argon, concentrated down. The resulting residue was dissolved in ethyl acetate, washed with H₂O (3×). After shaking, the aqueous layer was drained off. The EtOAc layer was then washed with water (3×), brine and concentrated. The resulting oil was dissolved in DCM:CH₃CN and flushed through a column of silica gel (80 g) using DCM:CH₃CN 1:1 to yield the desired product.

Step 3 Tert-butyl 8-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P07

Tert-butyl 8-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01 starting from tert-butyl 8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 402 [M+H]⁺

P08 Tert-butyl 7-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1 Methyl 2-(2-ethoxy-2-oxoethoxy)-4-iodobenzoate

Ethyl bromoacetate (80 mL; 0.72 mol, Aldrich, 98%) was added to a solution of 4-iodo-methylsalicylate (200 g, 0.72 mol; 1.0 eq), potassium carbonate (198 g, 2 eq, 1.44 mol) and potassium iodide (17.8 g 0.107 mol 0.15 eq) in acetone under nitrogen. The reaction was stirred at 50° C. for 5 h and at r.t. for 16 h. The reaction mixture was filtered and the solid was washed with acetone. The liquors were concentrated to a dark brown oil and dried under house vacuum to afford 241 g of methyl 2-(2-ethoxy-2-oxoethoxy)-4-iodobenzoate. ¹H-NMR (400 MHz, CDCl₃): δ 1.31 (t, 3H), 3.89 (s, 3H), 4.28 (q, 2H), 4.70 (s, 2H), 7.22 (d, 1H), 7.41 (dd, 1H), 7.54 (d, 1H).

Step 2 6-iodo-1-benzofuran-3(2H)-one

A solution of methyl 2-(2-ethoxy-2-oxoethoxy)-4-iodobenzoate (241.6 g, 0.664 mol) in toluene (500 mL) was added to a solution of LHMDS in THF (1.38 l, 1.0M; 1.33 mol; 2.0 eq) over 1 hour 35 minutes with an ice bath in place to keep the temperature at 21-25° C. After 30 min stirring, the solvent was concentrated and toluene was added. The suspension was filtered, the solids were washed with of toluene (300 mL) and dried under house vacuum to afford 256 g of brownish solid. This solid was then suspended in a mixture of H₂O (20 mL) and ethanol (830 mL) and sodium hydroxide pellets were added (166 g; 4.15 mol; 6.25 eq). After stirring at 80° C. for 1.5 h, 6 N HCl (885 mL; 5.31 mol; 8.0 eq) was added over 1 hour 35 minutes at 25-27° C. After 50 min stirring, the suspension was filtered, the resulting solids taken up in 495 mL of 1N HCl (495 mL), H₂O (165 mL) and EtOH (205 mL). This solution was heated to 60° C. for 30 min and then cooled down to 21° C. before filtration. The orange solid was washed with H₂O (150 mL) and dried to afford 153 g of the expected product. ¹H-NMR (400 MHz, CDCl₃): δ 4.60 (s, 2H), 7.37 (d, 1H), 7.45 (d, 1H), 7.60 (s, 1H).

Step 3 6-iodo-1-benzofuran-3-carbonitrile

Sodium hydride (37.3 g; 0.886 mol; 1.2 eq; 60 wt % dispersion in oil) was suspended in hexanes (120 mL) under N₂. The sodium hydride was allowed to settle and the hexanes were syringed out of the flask and dry THF (100 mL) added. The NaH was washed again and the THF decanted. A fresh portion of dry THF (300 mL) was added and diethylcyanomethylphosphonate (0.886; 1.2 eq) was added drop wise over 35 min while keeping the temperature at 20-22° C. A solution of 6-iodo-1-benzofuran-3(2H)-one (192.0 g; 0.74 mol) in THF (1.75 L) then added over 35 min at 15-25° C. After 30 min stirring, 6N HCl (750 mL), MTBE (750 mL), and H₂O (500 mL) were added. The layers were separated, sodium sulfate was added to the organic layer. The organics were filtered and concentrated. The resulting red solids were suspended in MTBE (500 mL), washed four times with 1N HCl (400 mL). The solvent was evaporated to afford 214 g of the title product. ¹H-NMR (400 MHz, CDCl₃): δ 3.75 (bs, 1H), 7.34 (d, 1H), 7.60 (s, 1H), 7.62 (dd, 1H), 7.91 (d, 1H).

Step 4 2-(6-iodo-1-benzofuran-3-yl)ethanamine P09

A solution of diborane (1.0 M; 806 mL; 0.806 mol; 2.4 eq) in THF was added dropwise to a solution of 6-iodo-1-benzofuran-3-carbonitrile (95 g, 0.336 mol) in THF (730 mL) over 26 min at 1.4-4.0° C. After 20 h stirring at r.t., methanol was added over 15 minutes while keeping the reaction at 18-25° C. and the solvent was evaporated. The remaining orange liquid was taken up in 3N HCl in MeOH (417 mL; 1.25 mol; 3.72 eq), stirred for 20 h at 30° C. and 48 h at room temperature. The solvent was evaporated and the residue suspended in MTBE (450 mL). After stirring for 1.5 h, the solution was filtered. The solids were washed with MTBE (40 mL) and dried under house vacuum to provide 80.9 g of the title product as a hydrochloric acid salt. ¹H-NMR (400 MHz, CDCl₃): δ 3.06 (t, 2H), 3.27 (t, 2H), 7.46 (bd, 1H), 7.61 (bd, 1H), 7.68 (bs, 1H), 7.91 (bs, 1H).

Step 5 7-iodo-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine

Paraformaldehyde (8.9 g, 0.297 mol) was added to a solution of 2-(6-iodo-1-benzofuran-3-yl)ethanamine hydrochloride (80 g; 0.247 mol) in 1N HCl (500 mL) under N₂. After 2 h stirring at 70° C., another portion of paraformaldehyde (740 mg) was added. The reaction mixture was cooled down to r.t., filtered, the resulting solid was washed with 1N HCl (100 mL), dried overnight under house vacuum to afford 76.7 g of the title product as a hydrochloric acid salt. ¹H-NMR (400 MHz, CDCl₃): δ 2.06 (bt, 2H), 2.92 (bt, 2H), 4.37 (s, 2H), 7.45 (d, 1H) 7.62 (dd, 1H), 8.05 (d, 1H), 10.04 (bs, 2H).

Step 6 Tert-butyl 7-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P08

Di-tert-butyl dicarbonate (50.4 g, 0.27 mol) was added slowly to a solution of 6-iodo-1-benzofuran-3(2H)-one hydrochloride (75 g, 0.23 mol) and triethylamine (68 mL, 0.46 mol; 2.0 eq.) in chloroform (460 mL). After 1 h stirring, the solvent was evaporated and the residue purified on silica gel eluting with hexane:ethyl acetate (95:5) and hexane:ethyl acetate (90:10). 68.7 g of the title product. MS m/z 400 [M+H]⁺

P10 Tert-butyl[2-(6-iodo-1-benzofuran-3-yl)ethyl]carbamate

Synthesized as described for tert-butyl 7-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 2-(6-iodo-1-benzofuran-3-yl)ethanamine hydrochloride. MS m/z 332 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.43 (s, 9H), 2.85 (t, 2H), 3.43 (q, 2H), 4.62 (bs, 1H), 7.31 (d, 1H), 7.39 (s, 1H), 7.54 (dd, 1H), 7.84 (d, 1H).

P11 Tert-butyl 7-iodo-1-methyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1 7-iodo-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine

Synthesized as described for 7-iodo-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine using acetaldehyde. ¹H-NMR (400 MHz, CDCl₃): δ 1.60 (d, 3H), 2.92 (m, 2H), 3.37 (m, 1H), 3.59 (m, 1H), 4.77 (m, 1H), 7.46 (d, 1H), 7.64 (dd, 1H), 8.07 (d, 1H), 9.58 (bs, 1H), 10.02 (bs, 1H).

Step 2 Tert-butyl 7-iodo-1-methyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P11

Synthesized as described for 7-iodo-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine starting from 7-iodo-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine. MS m/z 414 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.46 (d, 3H), 1.50 (s, 9H), 2.59 (m, 1H), 2.73 (m, 1H), 3.06 (m, 1H), 4.36 (bd, 1H), 5.23 (bd, 1H), 7.18 (d, 1H), 7.52 (d, 1H), 7.79 (s, 1H).

P12 Tert-butyl 6-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Synthesized as described for tert-butyl 6-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine 2(1H)-carboxylate using 2-(5-iodo-1-benzofuran-3-yl)ethanamine. MS m/z 400 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.50 (s, 9H), 2.54 (m, 2H), 3.55 (m, 2H), 4.52 (m, 2H), 7.20 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 1.8 Hz, 1H), 7.77 (s, 1H).

P13 2-(5-iodo-1-benzofuran-3-yl)ethanamine

Synthesized as described for 2-(6-iodo-1-benzofuran-3-yl)ethanamine using methyl 2-hydroxy-5-iodobenzoate. ¹H-NMR (400 MHz, DMSO-d₆): δ 2.91 (t, J=7.7 Hz, 2H), 3.11 (m, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.8 Hz, 1H), 7.90 (s, 1H), 8.09 (bs, 2H), 8.11 (d, J=1.7 Hz, 1H).

P14 Tert-butyl[2-(5-iodo-1-benzofuran-3-yl)ethyl]carbamate

Synthesized as described for tert-butyl[2-(6-iodo-1-benzofuran-3-yl)ethyl]carbamate using 2-(5-iodo-1-benzofuran-3-yl)ethanamine. ¹H-NMR (400 MHz, CDCl₃): δ 1.44 (s, 9H), 2.84 (t, 1H), 3.43 (q, 2H), 4.62 (bs, 1H), 7.25 (d, 1H), 7.43 (s, 1H), 7.56 (dd, 1H), 7.88 (d, 1H).

P15 Tert-butyl 6-iodo-1-methyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Synthesized as described for tert-butyl 7-iodo-1-methyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 6-iodo-1-methyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine. MS m/z 414 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ 1.47 (d, J=6.8 Hz, 3H), 1.51 (s, 9H), 2.57 (m, 1H), 2.71 (m, 1H), 3.05 (m, 1H), 4.38 (m, 1H), 5.21 (m, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.6, 1.8 Hz, 1H), 7.76 (s, 1H).

P20 Tert-butyl 7-iodo-4,4-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1 2-(6-Iodo-benzofuran-3-yl)-2-methyl-propionitrile

To a solution of (6-iodo-benzofuran-3-yl)-acetonitrile (1.42 g, 5.02 mmol) in tetrahydrofuran (25 mL) at −50° C. was added lithium hexamethyldisilazide (1.03M solution, 10 mL, 10.3 mmol, the mixture turned green). The mixture was stirred at −60° C. for 20 minutes and was cooled to at −78° C. Methyl iodide (2 mL, 30 mmol) was added dropwise and the mixture was slowly allowed to warm up. After 3 h (temp. was below 0° C.) the mixture was quenched with saturated ammonium chloride solution. The mixture was extracted from ethyl acetate and combine organic was washed with water and brine. After drying, solvent was evaporated and the crude product was purified by ISCO (80 g column, hexane with 7.5% ethyl acetate). 2-(6-Iodo-benzofuran-3-yl)-2-methyl-propionitrile was obtained as syrup (1.32 g).

Step 2 2-(6-Iodo-benzofuran-3-yl)-2-methyl-propylamine P21

Synthesized as described for 2-(6-iodo-1-benzofuran-3-yl)ethanamine using 2-(6-iodo-benzofuran-3-yl)-2-methyl-propionitrile as the starting material.

Step 3 Tert-butyl 7-iodo-4,4-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P20

Synthesized as described for tert-butyl 7-iodo-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate using 2-(6-iodo-benzofuran-3-yl)-2-methyl-propylamine as the starting material. MS m/z 372 [M−tBu+H]⁺

P26 7-Iodo-4-methyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Step 1 2-(6-Iodo-benzofuran-3-yl)-propionitrile

To a solution of (6-iodo-benzofuran-3-yl)-acetonitrile (1 g, 4 mmol) in tetrahydrofuran (25 mL) at −50° C. was added Lithium hexamethyldisilazide (1.03M solution, 10 mL). The mixture was stirred at −60° C. for 20 minutes and was cooled to at −78° C. Methyl iodide (0.30 mL, 4.8 mmol) was added dropwise and the mixture was slowly allowed to warm up. After 3 h the mixture was quenched with saturated ammonium chloride solution and was extracted from ethyl acetate. Combined organics were washed with water and brine. After drying, solvent was evaporated and the crude product was purified by ISCO (7.5% ethyl acetate in hexane) to afford. 2-(6-Iodo-benzofuran-3-yl)-propionitrile (547 mg, 52%). mp 71-72° C.; MS m/z: 298 [M+H]⁺

Step 2 7-Iodo-4-methyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester P26

Synthesized as described for tert-butyl 7-iodo-4,4-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate using 2-(6-Iodo-benzofuran-3-yl)-propionitrile 2-(6-Iodo-benzofuran-3-yl)-2-methyl-propylamine.

P22 (6-Iodo-7-methoxy-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

To a solution of 7-methoxy-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (500 mg, 2 mmol) in methanol (7 mL, 200 mmol) was added dropwise a solution of iodine monochloride (340 mg, 2.1 mmol) in 5 ml of methanol at RT. The mixture was stirred overnight at RT. After 18 h, the solvent was removed and the crude reaction mixture was treated with 50 mL of acetonitrile, di-tert-butyl dicarbonate (0.5 mL) and 10 mg of DMAP (10 mg). The mixture was stirred overnight at RT. After 18 h, solvent was removed and the crude product was purified by ISCO chromatography (Hexane:EtOAc 70:30) which was obtained as a syrup (321 mg, 45%). MS m/z 454 [M+H]⁺

P23 Tert-butyl 7-iodo-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1 (2-Acetyl-5-methoxy-phenoxy)-acetic acid ethyl ester

Into a Round bottom flask was added Ethanone, 1-(2-hydroxy-4-methoxyphenyl)-ethanone (40.01 g, 0.241 mol), ethyl bromoacetate (28.17 mL, 0.2540 mol), potassium carbonate (69.6 g, 0.504 mol), and N,N-Dimethylformamide (200 mL, 2 mol). The reaction was heated at 90° C. for 6 h before cooling to RT overnight. The reaction was poured into ice/water and extracted with ethyl ether (twice). The combined ether extracts were dried, filtered and concentrated. The resulting solid was triturated in hexanes, filtered and dried. The product was used in the next reaction step without further purification.

Step 2 [2-(-2-Cyano-1-methyl-vinyl)-5-methoxy-phenoxy]-acetic acid ethyl ester

To a slurry of Sodium hydride, 60% disp. in mineral oil (7.44 g, 0.186 mol) in Tetrahydrofuran (200 mL, 2 mol) was added and a solution of diethyl cyanomethylphosphonate (30.0 mL, 0.186 mol) in THF (50 mL) slowly, hydrogen was released. After addition and 10 minutes at RT the reaction was cooled at 0° C. and a mixture of (2-acetyl-5-methoxy-phenoxy)-acetic acid ethyl ester (44.6 g, 0.177 mol) in tetrahydrofuran (150 mL) was added dropwise. After 2 hr at 0° C., the reaction was transferred into ice/water and extracted with diethylether. The ether layer was washed with brine, dried, filtered and concentrated. The product was used in the next reaction step without further purification.

Step 3 3-Cyano-6-methoxy-3-methyl-2,3-dihydro-benzofuran-2-carboxylic acid ethyl ester

To a mixture of [2-(2-cyano-1-methyl-vinyl)-5-methoxy-phenoxy]-acetic acid ethyl ester (39 g, 0.14 mol), separated into 6 tubes with 6.5 gm in each, was added ethanol (7 mL, 0.1 mol) and then sodium hydride (15 mg, 0.38 mmol, 60% in mineral oil) was added slowly and the reaction was heated at 80° C. for 1 h. The reaction mixtures were cooled to RT, transferred into ice and extracted with diethylether. The ether layers were washed with sat. sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to a brown oil. The product was used in the next reaction step without further purification.

Step 4 7-Methoxy-4a-methyl-3,4,4a,9a-tetrahydro-2Hbenzo[4,5]furo[2,3-c]pyridine-1-one

A mixture of 3-cyano-6-methoxy-3-methyl-2,3-dihydro-benzofuran-2-carboxylic acid ethyl ester (33.53 g, 0.1283 mol), platinum dioxide (250 mg, 0.0011 mol) and acetic acid (50 mL, 0.9 mol) were hydrogenated on a paar shaker at 55 psi for 3 h. The reaction mixture was filtered through a plug of Celite. The filtrate was concentrated, the residue was dissolved in ethyl acetate, washed with water, bicarbonate, brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified on silica gel column (300 g) and eluting first with ethyl acetate and then 10% methanol/DCM. The product was used in the next reaction step without further purification.

Step 5 7-Methoxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine

To a solution of 7-methoxy-4a-methyl-3,4,4a,9a-tetrahydro-2Hbenzo[4,5]furo[2,3-c]pyridine-1-one (1.0 g, 4.30 mmol) in tetrahydrofuran (3 mL) was slowly added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (2 mL). After 30 min stirring another portion of 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (1 mL) was added and the reaction was stirred for 2 h. The reaction was transferred into ice, 6N aqueous HCl was added followed by ethyl acetate. The aqueous layer was basified by adding NaOH and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated to provide a colorless oil. The product was used in the next reaction step without further purification.

Step 6 Tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Synthesized as described for tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from 7-Methoxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine.

Step 7 Tert-butyl 7-iodo-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P23

Synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 360 [M-tBu+H]⁺

P24 Tert-butyl 6-iodo-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Synthesized as described for tert-butyl 7-iodo-4a-methyl-3,4,4a,9a tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from tert-butyl 6-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 360 [M-tBu+H]⁺

P25 Tert-butyl 6-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Synthesized as described for tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate and as described in J. Med. Chem., 1989, 32, 2221-2226 starting from 1-(2-hydroxy-3-methoxyphenyl)-ethanone. MS m/z 250 [M-tBu+H]⁺

P30 tert-butyl 7-iodo-1,1-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate

Step 1

To a solution of 2-(6-iodo-benzofuran-3-yl)-ethylamine (4.20 g, 14.63 mmol) in methanol (60.0 mL, 1.48 mol) was added acetone (1.63 mL) and the reaction mixture was stirred at rt. After 2 days the solvent was evaporated. The residue was dissolved in a mixture of TFA (7.0 mL) and DCE (70.0 mL) and heated to reflux. After 20 h the reaction mixture was cooled down and basified with 5M aq. NaOH. The layers were separated and the aqueous phase extracted with DCM. The combined organic layers was dried (Na₂SO₄) and the solvent was evaporated. The residue was purified on a silica gel column eluting with DCM-MeOH—NH₄OH to afford 7-iodo-1,1-dimethyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine as an off-white solid. mp 97-98° C.; MS m/z 328 [M+H]⁺.

Step 2

To a solution of 7-iodo-1,1-dimethyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (0.420 g, 1.28 mmol) in THF (10.0 mL) was added water (10.0 mL), sodium bicarbonate (0.647 g, 7.70 mmol) followed by di-tert-butyldicarbonate (0.420 g, 1.92 mmol). After 16 h stirring, the solution was concentrated and extracted with DCM. The organic layer was dried over Na₂SO₄ and the solvent was evaporated to give the title product. The product was used in the next reaction step without further purification. MS m/z 449 [M+H]⁺.

A01 7-iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran]

A solution of 2-(6-iodo-benzofuran-3-yl)-ethylamine (1.00 g, 3.48 mmol) and dihydro-pyran-3-one (1.05 g, 10.4 mmol) in trifluoroacetic acid (4.00 mL) was heated at 80° C. for 15 h. The reaction mixture was cooled down, 1M aqueous NaOH was added and the mixture was extracted with DCM. The solvent was evaporated and the residue was purified by silica gel chromatography eluting with DCM-MeOH—NH₄OH to afford the title product. mp 131-137° C. dec.; MS m/z 370 [M+H]⁺

Chiral separation of 7-iodo-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] A01 was performed using SFC chromatography on a chiral column as described in the general method. Enantiomer 1 A02, MS m/z 370 [M+H]⁺ and Enantiomer 2 A03, MS m/z 370 [M+H]⁺ were obtained.

The following examples in the table were prepared as described by the above synthetic procedure. Enantiomers were obtained using SFC chromatography on a chiral column as described in the general method and starting from the corresponding stereoisomer mixture.

MS m/z Prep Chemical name [M + H]⁺ Stereochemistry Scaffold Starting material A04 7-iodo-3,4-dihydro-2H-spiro[1- 340 P09 cyclobutanone benzofuro[2,3-c]pyridine-1,1′- cyclobutane] A05 7-iodo-3,4-dihydro-2H-spiro[1- 342 P09 oxetan-3-one benzofuro[2,3-c]pyridine-1,3′- oxetane] A06 1-ethyl-7-iodo-1-methyl-1,2,3,4- 342 P09 butan-2-one tetrahydro[1]benzofuro[2,3- c]pyridine A07 7-iodo-3,4-dihydro-2H-spiro[1- 354 P09 cyclopentanone benzofuro[2,3-c]pyridine-1,1′- cyclopentane] A08 1-cyclopropyl-7-iodo-1-methyl- 354 P09 1- 1,2,3,4-tetrahydro[1]benzofuro[2,3- cyclopropylethanone c]pyridine A09 7-iodo-3,4,4′,5′-tetrahydro-2H- 356 racemic P09 dihydrofuran-3(2H)- spiro[1-benzofuro[2,3-c]pyridine- one 1,3′-furan] A10 7-iodo-3,4,4′,5′-tetrahydro-2H- 356 enantiomer 1 P09 dihydrofuran-3(2H)- spiro[1-benzofuro[2,3-c]pyridine- one 1,3′-furan] A11 7-iodo-3,4,4′,5′-tetrahydro-2H- 356 enantiomer 2 P09 dihydrofuran-3(2H)- spiro[1-benzofuro[2,3-c]pyridine- one 1,3′-furan] A12 7-iodo-1-(methoxymethyl)-1-methyl- 358 P09 1-methoxypropan-2- 1,2,3,4-tetrahydro[1]benzofuro[2,3- one c]pyridine A13 1-(ethoxymethyl)-7-iodo-1,2,3,4- 358 P09 1,1,2- tetrahydro[1]benzofuro[2,3- triethoxyethane c]pyridine A14 7-iodo-1-(methoxymethyl)-1-methyl- 358 P09 1-methoxypropan-2- 1,2,3,4-tetrahydro[1]benzofuro[2,3- one c]pyridine A15 1-(difluoromethyl)-7-iodo-1-methyl- 364 racemic P09 1,1-difluoropropan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-one c]pyridine A16 1-(difluoromethyl)-7-iodo-1-methyl- 364 enantiomer 1 P09 1,1-difluoropropan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-one c]pyridine A17 1-(difluoromethyl)-7-iodo-1-methyl- 364 enantiomer 2 P09 1,1-difluoropropan- 1,2,3,4-tetrahydro[1]benzofuro[2,3- 2-one c]pyridine A18 1,1-bis(fluoromethyl)-7-iodo-1,2,3,4- 364 Racemic P09 1,3-difluoropropan- tetrahydro[1]benzofuro[2,3- 2-one c]pyridine A19 7-iodo-1-methyl-1-(2-methylpropyl)- 370 Racemic P09 4-methylpentan-2- 1,2,3,4-tetrahydro[1]benzofuro[2,3- one c]pyridine A20 7-iodo-1-methyl-1-(trifluoromethyl)- 382 Racemic P09 1,1,1- 1,2,3,4-tetrahydro[1]benzofuro[2,3- trifluoropropan-2- c]pyridine one A21 7-iodo-4,4-dimethyl-3,4,4′,5′- 384 Racemic P09 dihydrofuran-3(2H)- tetrahydro-2H-spiro[1- one benzofuro[2,3-c]pyridine-1,3′-furan] A22 7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H- 386 P09 tetrahydro-4H- spiro[1-benzofuro[2,3-c]pyridine- thiopyran-4-one 1,4′-thiopyran] A23 7-iodo-1,1-bis(methoxymethyl)- 388 P09 1,3- 1,2,3,4-tetrahydro[1]benzofuro[2,3- dimethoxypropan-2- c]pyridine one A24 7-iodo-4,4-dimethyl-2′,3,3′,4,5′,6′- 398 P09 tetrahydro-4H- hexahydro-2H-spiro[1- pyran-4-one benzofuro[2,3-c]pyridine-1,4′-pyran] A25 2-(7-iodo-1-methyl-1,2,3,4- 399 Racemic P09 N,N-dimethyl-3- tetrahydro[1]benzofuro[2,3-c]pyridin- oxobutanamide 1-yl)-N,N-dimethylacetamide A26 1-(7-iodo-3,4-dihydro-1′H,2H- 411 P09 1-acetylpiperidin-4- spiro[1-benzofuro[2,3-c]pyridine- one 1,4′-piperidin]-1′-yl)ethanone A27 6-iodo-1,1-dimethyl-1,2,3,4- 328 P13 propan-2-one tetrahydro[1]benzofuro[2,3- c]pyridine A28 7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H- 370 Racemic P09 tetrahydro-4H- spiro[1-benzofuro[2,3-c]pyridine- pyran-4-one 1,4′-pyran] A29 7-iodo-4,4-dimethyl-1-(tetrahydro- 412 Racemic P21 tetrahydro-2H- 2H-pyran-4-yl)-1,2,3,4- pyran-4- tetrahydro[1]benzofuro[2,3- carbaldehyde c]pyridine A30 7-iodo-4,4-dimethyl-3,4,4′,5′- 384 Racemic P21 dihydrofuran-3(2H)- tetrahydro-2H-spiro[1- one benzofuro[2,3-c]pyridine-1,3′-furan] A31 6-iodo-3,4,4′,5′-tetrahydro-2H- 356 Racemic P13 dihydrofuran-3(2H)- spiro[1-benzofuro[2,3-c]pyridine- one 1,3′-furan]

A32 7-iodo-2,2′,3,3′,4,5′,6′,9-octahydrospiro[beta-carboline-1,4′-pyran]

A solution of [2-(6-Iodo-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (500.0 mg, 1.294 mmol) was stirred into a mixture of DCE (2.0 mL) and TFA (2.0 mL) for 10 min. Tetrahydro-4H-pyran-4-one (360.0 uL, 3.88 mmol) was added. The reaction mixture was stirred at 40° C. for one hour, then at 50° C. for two hours and finally at 60° C. for one hour. The reaction solution was then concentrated down and the product was used in the next step without further purification. MS m/z 369 [M+H]⁺.

The following examples were prepared essentially as described directly above.

MS m/z Preparation Name [M + H]⁺ Starting material A32 7-iodo-2,2′,3,3′,4,5′,6′,9- 369 tetrahydro-4H-pyran-4-one octahydrospiro[beta-carboline-1,4′- pyran] A33 7-iodo-2,3,4,5′,6′,9-hexahydro-4′H- 369 tetrahydro-4H-pyran-3-one spiro[beta-carboline-1,3′-pyran] A34 7-iodo-2,3,4,4′,5′,9- 355 dihydrofuran-3(2H)-one hexahydrospiro[beta-carboline-1,3′- furan]

B01 Tert-butyl-7-iodo-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan]-2-carboxylate enantiomer 2

To a solution of 7-iodo-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan] (790 mg, 2.2 mmol) in anhydrous 1,4-dioxane (12 mL), N,N-diisopropylethylamine (1.16 mL, 6.67 mmol) and di-tert-butyldicarbonate (1.28 mL, 5.56 mmol) were added. After 1 h stirring at 80° C. another portion of di-tert-butyldicarbonate (1.28 mL, 5.56 mmol) was added. After 3 h stirring at 80° C., the reaction was concentrated down. The crude product was suspended in a mixture of DCM (14 mL) and a solution of DMAP in H₂O (0.05M, 10 mL). The resulting biphasic mixture was vigorously stirred for 1 h. The aqueous layer was removed, the organic layer was washed with saturated ammonium chloride (2×), water and brine, dried over anhydrous magnesium sulfate and concentrated to yield a tan solid. MS m/z 477.90 [M+Na]⁺.

The following examples in the table were prepared as described in the above synthetic procedure. Enantiomers B16 and B17 were obtained from preparation B15 using SFC chromatography on a chiral column according to the general method.

MS m/z Starting Preparation Name [M + H]⁺ Stereochemistry material B01 tert-butyl (1R)-7-iodo- 456 enantiomer 2 A11 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan]-2- carboxylate B02 tert-butyl (1S)-7-iodo- 456 enantiomer 1 A10 3,4,4′,5′-tetrahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,3′-furan]-2- carboxylate B03 tert-butyl 7-iodo-3,4,4′,5′- 456 racemic A09 tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,3′-furan]-2-carboxylate B04 tert-butyl 7-iodo-3,4,5′,6′- 470 enantiomer 1 A02 tetrahydro-2H,4′H-spiro[1- benzofuro[2,3-c]pyridine- 1,3′-pyran]-2-carboxylate B05 tert-butyl 7-iodo-3,4,5′,6′- 470 enantiomer 2 A03 tetrahydro-2H,4′H-spiro[1- benzofuro[2,3-c]pyridine- 1,3′-pyran]-2-carboxylate B06 tert-butyl 7-iodo- 470 A37 2′,3,3′,4,5′,6′-hexahydro-2H- spiro[1-benzofuro[2,3- c]pyridine-1,4′-pyran]-2- carboxylate B07 tert-butyl 6-iodo-3,4,4′,5′- 456 racemic A31 tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,3′-furan]-2-carboxylate B08 tert-butyl 7-iodo-4,4- 498 racemic A24 dimethyl-2′,3,3′,4,5′,6′- hexahydro-2H-spiro[1- benzofuro[2,3-c]pyridine- 1,4′-pyran]-2-carboxylate B15 tert-butyl 7-iodo-4,5′,6′,9- 469 racemic A33 tetrahydro-4′H-spiro[beta- carboline-1,3′-pyran]-2(3H)- carboxylate B16 tert-butyl 7-iodo-4,5′,6′,9- 469 enantiomer 1 B15 tetrahydro-4′H-spiro[beta- carboline-1,3′-pyran]-2(3H)- carboxylate B17 tert-butyl 7-iodo-4,5′,6′,9- 469 enantiomer 2 B15 tetrahydro-4′H-spiro[beta- carboline-1,3′-pyran]-2(3H)- carboxylate

B09 {2-[6-(3-Fluoro-benzenesulfonyl)-benzofuran-3-yl]-ethyl}-carbamic acid tert-butyl ester

Synthesized as described for 6-(3-chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester starting from tert-butyl[2-(6-iodo-1-benzofuran-3-yl)ethyl]carbamate and purified using preparative LC-MS. MS m/z 420 [M+H]⁺

The following examples were prepared essentially as described directly above.

MS m/z Prep Chemical name [M + H]⁺ Scaffold Starting mat B09 tert-butyl (2-{6-[(3-fluorophenyl)sulfonyl]-1- 420 P10 3-fluorobenzenethiol benzofuran-3-yl}ethyl)carbamate B10 tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1- 420 P14 3-fluorobenzenethiol benzofuran-3-yl}ethyl)carbamate B11 tert-butyl (2-{6-[(3-chlorophenyl)sulfonyl]-1- 436 P10 3-chlorobenzenethiol benzofuran-3-yl}ethyl)carbamate B12 tert-butyl (2-{5-[(3-chlorophenyl)sulfonyl]-1- 436 P14 3-chlorobenzenethiol benzofuran-3-yl}ethyl)carbamate B13 tert-butyl {2-[6-(phenylsulfonyl)-1- 402 P10 benzenethiol benzofuran-3-yl]ethyl}carbamate B14 tert-butyl (2-{6-[(3-fluorophenyl)sulfonyl]-1H- 419 [2-(6-Iodo-1H- 3-fluorobenzenethiol indol-3-yl}ethyl)carbamate indol-3-yl)- ethyl]- carbamic acid tert-butyl ester

C01 1,1-Dimethyl-7-triisopropylsilanylsulfanyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Anhydrous dioxane was bubbled with Argon for 1 h before being used. Triisopropylsilanethiol (4.00 mL, 18.6 mmol) was dissolved into anhydrous 1,4-dioxane (15 mL) and a solution of lithium hexamethyldisilazide in THF (1.0 M 17.7 mL, 17.7 mmol) was added slowly. The reaction was stirred for 2.5 h. A portion of the lithium triisopropylsilanethiolate solution (15.4 mL, 7.70 mmol) was added to a suspension of 7-iodo-1,1-dimethyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (3.00 g, 7.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.70 mmol) in 1,4-dioxane (10 mL) under argon. The reaction mixture was stirred at 60° C. for 2 h and the solvent was evaporated. The residue was triturated with anhydrous hexane, filtered through a plug of Celite and the filtrate was concentrated down to yield 4.48 g of 1,1-dimethyl-7-triisopropylsilanylsulfanyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester. This product was used in the next step without further purification. MS m/z 490 [M+H]⁺

The following examples in the table were prepared as described in the above synthetic procedure.

Starting Prep Name MS m/z Stereochemistry material C01 tert-butyl 1,1-dimethyl-7-[(tripropan-2- 434 [M − tBu + H]⁺ P30 ylsilyl)sulfanyl]-3,4-dihydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate C02 tert-butyl 7-[(tripropan-2-ylsilyl)sulfanyl]- 486 [M + Na]⁺ racemate P01 3,4,4a,9a-tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate C03 tert-butyl 7-[(tripropan-2-ylsilyl)sulfanyl]- 464 [M + Na]⁺ enantiomer 1 P03 3,4,4a,9a-tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate C04 tert-butyl 7-[(tripropan-2-ylsilyl)sulfanyl]- 464 [M + Na]⁺ enantiomer 2 P04 3,4,4a,9a-tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate C05 tert-butyl 4a-methyl-7-[(tripropan-2- 500 [M + Na]⁺ P23 ylsilyl)sulfanyl]-3,4,4a,9a- tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)- carboxylate C06 tert-butyl 7-[(tripropan-2-ylsilyl)sulfanyl]-3,4- 447 [M − Me + H]⁺ P08 dihydro[1]benzofuro[2,3-c]pyridine-2(1H)- carboxylate C07 tert-butyl 6-[(tripropan-2-ylsilyl)sulfanyl]-3,4- 447 [M − Me + H]⁺ P12 dihydro[1]benzofuro[2,3-c]pyridine-2(1H)- carboxylate C08 tert-butyl 4,4-dimethyl-7-[(tripropan-2- P20 ylsilyl)sulfanyl]-3,4-dihydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate C09 4,4-dimethyl-7-[(tripropan-2-ylsilyl)sulfanyl]- 446 [M + H]⁺ A21 3,4,4′,5′-tetrahydro-2H-spiro[1- benzofuro[2,3-c]pyridine-1,3′-furan]

SM01 3-Trifluoromethyl-5-triisopropylsilanylsulfanyl-pyridine

Anhydrous toluene was bubbled with Argon for 1 h before being used. Palladium acetate (0.050 g, 0.22 mmol), triphenylphosphine (0.255 g, 0.973 mmol), cesium carbonate (1.87 g, 5.75 mmol) and 3-bromo-5-trifluoromethyl-pyridine (1.00 g, 4.42 mmol) were introduced into a 50 mL round bottom flask under argon. Toluene (10 mL) and triisopropylsilanethiol (1.23 mL, 5.75 mmol) were added. The reaction was stirred at 100° C. overnight, then cooled to room temperature and diluted with hexanes. The suspension was filtered through a plug of Celite. The filtrate was concentrated down to afford 3-trifluoromethyl-5-triisopropylsilanylsulfanyl-pyridine which was used in the next reaction step without further purification.

The following examples were prepared essentially as described immediately above.

Preparation Chemical name Starting material SM02 (2,3-dihydro-1,4-benzodioxin-5- 5-bromo-2,3-dihydro- ylsulfanyl)(tripropan-2-yl)silane 1,4-benzodioxine SM03 [(3,5-difluoro-2-methoxyphenyl)- 1-bromo-3,5-difluoro- sulfanyl](tripropan-2-yl)silane 2-methoxybenzene SM04 [(2,2-difluoro-1,3-benzodioxol-4- 4-bromo-2,2-difluoro- yl)sulfanyl](tripropan-2-yl)silane 1,3-benzodioxole

SM05 (3,5-Dimethoxy-phenylsulfanyl)-triisopropyl-silane

To a solution of triisopropylsilanethiol (0.49 g, 2.6 mmol) in 1,4-dioxane (5 mL, 60 mmol) was added lithium hydride (23 mg, 2.9 mmol). After 10 minutes, 1-bromo-3,5-dimethoxy-benzene (500 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (270 mg, 0.23 mmol) were added and the reaction mixture was heated to 60° C. for 16 h. The reaction mixture was diluted with DCM, filtered and concentrated. The resulting residue was dissolved in DCM and purified using silica gel chromatographie (40 g silica gel column) eluting with hexanes:DCM (3:1) to afford the title product.

SM06 [(2,3-difluorophenyl)sulfanyl](tripropan-2-yl)silane

Prepared as described for (1,2-dimethoxy-phenylsulfanyl)-triisopropyl-silane starting from 1,2-difluoro-3-iodobenzene.

SM07 2-Fluoro-3-isopropoxy-phenylsulfanyl)-triisopropyl-silane

Triisopropylsilanethiol (1.10 mL, 5.15 mmol) was added to a mixture of 1-bromo-2-fluoro-3-isopropoxy-benzene (1.00 g, 4.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (98.2 mg, 0.107 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (65 mg, 0.11 mmol) and a solution of lithium hexamethyldisilazide (1.2 equivalent) in toluene (8 mL,). The reaction mixture was stirred at 120° C. for 6 h. After cooling down to room temperature, the reaction mixture was filtered through a plug of alumina and eluted with diethylether. The solvent was evaporated and the resulting product (996 mg) was used in the next reaction step without further purification.

The following examples in the table were prepared as described in the above synthetic procedures.

Preparation Chemical name Starting material SM07 {[2-fluoro-3-(propan-2- 1-Bromo-2-fluoro-3- yloxy)phenyl]sulfanyl}- isopropoxy-benzene (tripropan-2-yl)silane SM08 {[3-(benzyloxy)-5- 1-(benzyloxy)-3-bromo- fluorophenyl]sulfanyl}- 5-fluorobenzene (tripropan-2-yl)silane SM09 {[(2E,4Z)-4-fluoro-5-(tetra- 4-({[(3Z,5E)-5-bromo- hydro-2H-pyran-4-ylmethoxy)- 4-fluorohepta-1,3,5-trien- hepta-2,4,6-trien-3-yl]sulfanyl}- 3-yl]oxy}methyl)tetra- (tripropan-2-yl)silane hydro-2H-pyran SM10 {[(2E,4Z)-4-chloro-5-(tetra- 4-({[(3Z,5E)-5-bromo- hydro-2H-pyran-4-ylmethoxy) 4-chlorohepta-1,3,5- hepta-2,4,6-trien-3-yl]sulfanyl}- trien-3-yl]oxy}methyl)- (tripropan-2-yl)silane tetrahydro-2H-pyran

The above procedures were found in or adapted from the following references: Adv. Synth. Catal., 2005, 47, 313-319 (aryl bromides); J. Am. Chem. Soc. Comm., 2006, 128, 2180-2181; and WO 03/004501 A2.

SM11 1-Fluoro-3-iodo-5-ethoxybenzene

(3-Ethoxy-5-fluorophenyl)boronic acid (2.5 g, 0.014 mol) was dissolved in THF (30 mL) and a solution of sodium iodide (4.1 g, 0.028 mol) in H₂O (15 mL) was added followed by a solution of chloramine T (7.8 g, 0.1 mol) in H₂O (15 mL). After 20 h stirring, the reaction mixture was extracted with diethylether (3×50 mL). The organic layers were combined and the solvent was evaporated. The resulting residue was triturated with hexanes (3×) and the hexanes layers were combined. The solvent was evaporated to yield 1-fluoro-3-iodo-5-ethoxybenzene as an orange oil. The product was used in the next reaction step without further purification.

The following examples were prepared essentially as described immediately above.

Preparation Chemical name Starting material SM11 1-ethoxy-3-fluoro-5- (3-ethoxy-5-fluorophenyl)- iodobenzene boronic acid SM12 2-fluoro-1-iodo-3- (2-fluoro-3-methoxyphenyl)- methoxybenzene boronic acid SM13 1-iodo-2-(propan-2- [2-(propan-2-yloxy)phenyl]- yloxy)benzene boronic acid SM14 1-fluoro-3-iodo-5- (3-fluoro-5-methoxyphenyl)- methoxybenzene boronic acid SM15 1-fluoro-3-iodo-5-(propan- [3-fluoro-5-(propan-2- 2-yloxy)benzene yloxy)phenyl]boronic acid SM16 1-fluoro-3-iodo-5-(2- [3-fluoro-5-(2- methylpropoxy)benzene methylpropoxy)phenyl]- boronic acid SM17 1-iodo-2-(2,2,2- [2-(2,2,2-trifluoroethoxy)- trifluoroethoxy)benzene phenyl]boronic acid SM18 1-fluoro-3-iodo-5-(2,2,2- [3-fluoro-5-(2,2,2- trifluoroethoxy)benzene trifluoroethoxy)phenyl]- boronic acid

SM19 3-Iodo-N-methylbenzamide

To a solution of 3-iodobenzoic acid (1.5 g, 6 mmol) in anhydrous DMF (10 mL) was added 1,1′-carbonyldiimidazole (1.2 g, 7.2 mmol). The reaction mixture was heated to 50° C. under an atmosphere of nitrogen for 1 h. Upon cooling to room temperature, a solution of methylamine in THF (2 M, 6 mL, 10 mmol) was added. The reaction was stirred at r.t. for 15 min and then transferred into a solution of cold, saturated ammonium chloride (200 mL). The resulting precipitate was collected by filtration and dried to afford the title compound as a white solid, mp 94-97° C.

SM20 3-Iodo-N,N-dimethylbenzamide

EDCI (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H]⁺.

SM21 2-Fluoro-6-iodo-N,N-dimethylbenzamide

2-Fluoro-6-iodobenzoylchloride 1.0 mL, 6.9 mmol was added dropwise to a solution of dimethylamine in THF (2.0 M 7.0 mL, 10 mmol). The reaction mixture was stirred for 16 h and then transferred into water. The resulting suspension was collected by filtration and dried to afford the title compound as a pale yellow solid. The product was used in the next reaction step without further purification. mp 86-89° C.

SM22 2-Fluoro-6-iodo-N-methylbenzamide

As described for 2-Fluoro-6-iodo-N,N-dimethylbenzamide SM21, mp 190-193° C.

SM23 1-Bromo-2-fluoro-3-isopropoxy-benzene

To a mixture of 3-bromo-2-fluoro-phenol (2 g, 10 mmol) and cesium carbonate (10 g, 40 mmol) in acetonitrile (20 mL) was added 2-bromopropane (4 mL, 50 mmol). The reaction mixture was stirred at 80° C. for 4 h. The mixture was filtered through a plug of Celite and eluted with ethyl acetate. The resulting solution was evaporated. The residue was purified by flash chromatography on silica gel and eluting with hexanes:EtOAc (1:1) to afford the title product (1.7 g).

SM 24 1-(Benzyloxy)-3-bromo-5-fluorobenzene

Prepared as described for 1-bromo-2-fluoro-3-isopropoxy-benzene SM23 using 3-bromo-5-fluorophenol and benzylbromide.

SM25 4-(3-Bromo-2-fluoro-phenoxymethyl)tetrahydropyran

Prepared as described for 1-bromo-2-fluoro-3-isopropoxy-benzene SM23 starting from 3-bromo-2-fluorophenol and 4-bromomethyltetrahydropyran. MS m/z: 290 [M+H]⁺.

SM26 4-(3-Bromo-2-chloro-phenoxymethyl)tetrahydropyran

Prepared as described for 4-(3-bromo-2-fluoro-phenoxymethyl)tetrahydropyran SM25 using 3-bromo-2-chlorophenol

SM27 1-Benzyloxy-3-iodo-5-isopropoxy-benzene

Step 1 3-Iodo-5-isopropoxy phenol

A mixture of 5-Iodo-benzene-1,3-diol (2 g, 8 mmol), 2-bromopropane (0.88 mL, 9.3 mmol) and potassium carbonate (1.3 g, 9.3 mmol) in DMF (15 mL, 190 mmol) was stirred at 65° C. After 18 h, the mixture was cooled to RT and the solvent was evaporated. The residue was dissolved in DCM, washed with water and brine. The solvent was evaporated and the residue was purified on silica gel using an ISCO instrument and eluting with hexanes:EtOAc (4:1) to afford the title product (841 mg). MS m/z: 279 [M+H]⁺.

Step 2 1-Benzyloxy-3-iodo-5-isopropoxy-benzene

A solution of 3-iodo-5-isopropoxy-phenol (840 mg, 3.0 mmol), benzyl bromide (0.4 mL, 3.3 mmol) and potassium carbonate (830 mg, 6.0 mmol) in DMF (15 mL, 190 mmol) was stirred at 65° C. for 18 h. The reaction mixture was cooled to RT, the solvent was removed and the residue was dissolved in DCM. The organic layer was washed with water and brine. The solvent was evaporated and the residue was purified on silica gel using an ISCO instrument and eluting with hexanes:EtOAc (4:1) to afford the title product SM27 (895 mg). MS m/z: 369 [M+H]⁺.

SM28 3-Benzyloxy-benzenethiol

3-Benzyloxyaniline (2.06 g, 10.3 mmol) was dissolved in water (40 ml) and concentrated HCl (8 ml). The solution was cooled to 0° C. and solution of sodium nitrite (778 mg, 11.3 mmol) in water (10 ml) was added. After 15 min stirring at 0° C., the mixture was added to a solution of potassium ethyl xanthate (3.1 g, 20 mmol) in water (10 ml), and heated to 65° C. for 30 min. After cooling to room temperature, the reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 1N NaOH and water, and dried over MgSO₄. The solvent was evaporated and the residue was dissolved in ethanol (50 ml). Potassium hydroxide (2 g, 40 mmol) was added and the mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature, concentrated, and partitioned between diethylether and water. The aqueous layer was acidified to pH 1 with concentrated HCl, and then extracted twice with methylene chloride. The combined organic layers were dried over MgSO₄ and the solvent was evaporated. The product was used in the next reaction step without further purification.

The following examples were prepared essentially as described immediately above.

Preparation Chemical name Starting mat SM29 3-(benzyloxy)-5- 3-(benzyloxy)-5- methoxybenzenethiol methoxyaniline SM30 3-(benzyloxy)-2- 3-(benzyloxy)-2- methylbenzenethiol methylaniline

SM31 5-Chloro-2-methoxy-benzenethiol

5-Chloro-2-methoxy-benzenesulfonyl chloride (1.0 g, 4.1 mmol) and triphenylphosphine (3.81 g, 14.5 mmol) were dissolved in THF (10 ml). Water (1.3 ml) was added and the mixture was stirred for 2 h at room temperature. The mixture was partitioned between 2N aqueous NaOH and diethylether. The aqueous phase was acidified to pH 1 with concentrated HCl and then extracted twice with methylene chloride. The combined organic layers were dried over MgSO₄ and the solvent was evaporated to afford the desired product (690 mg), which was used in the next reaction step without further purification. MS m/z: 175 [M+H]⁺

The following examples were prepared essentially as described directly above.

Preparation Chemical name Starting mat SM32 2,1,3-benzoxadiazole-4- 2,1,3-benzoxadiazole-4- thiol sulfonyl chloride SM33 3-chloro-2- 3-chloro-2-fluorobenzene- fluorobenzenethiol sulfonyl chloride SM34 1-methyl-1H-indole-7-thiol 1-methyl-1H-indole-7- sulfonyl chloride SM35 N-(3- 3-(acetylamino)benzene- sulfanylphenyl)acetamide sulfonyl chloride SM36 2,1,3-benzothiadiazole-4- 2,1,3-benzothiadiazole-4-- thiol sulfonyl chloride SM37 3-(1H-tetrazol-1- 3-(1H-tetrazol-1-yl)benzene- yl)benzenethiol sulfonyl chloride SM38 5-methyl-2,1,3- 5-methyl-2,1,3-benzothia- benzothiadiazole-4-thiol diazole- 4-sulfonyl chloride

SM39 3-Isopropoxy-5-methoxy-benzenethiol

Step 1 3-Amino-5-methoxyphenol

3,5-Dimethoxyaniline (9.97 g, 65.1 mmol) and sodium methyl mercaptide (9.1 g, 130 mmol) were dissolved in N-methylpyrrolidinone (60 ml). The reaction mixture was stirred at 140° C. for 1 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous Na₂HPO₄. The layers were separated and the organic layer was washed with water, dried over MgSO₄ and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with 50% EtOAc/hexanes to afford 3-amino-5-methoxyphenol (5.44 g). MS m/z: 140 [M+H]⁺

Step 2 3-Isopropoxy-5-methoxyaniline

To a solution of 3-amino-5-methoxyphenol (5.44 g, 39.1 mmol), isopropyl alcohol (3.6 ml, 47 mmol) and triphenylphosphine (12.0 g, 47 mmol) in THF, was added diethyl azodicarboxylate (7.4 ml, 47 mmol). The reaction mixture was stirred for 16 h and the solvent was removed. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/hexanes to afford the title compound (4.13 g). MS m/z: 182 [M+H]⁺

Step 3 3-Isopropoxy-5-methoxy-benzenethiol SM39

Prepared as described for 3-benzyloxy-benzenethiol SM28 starting from 3-isopropoxy-5-methoxyaniline. MS m/z: 199 [M+H]⁺

D01 7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Step 1 7-(3-Benzyloxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

As described for 6-(3-chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester starting from 3-benzyloxy-benzenethiol and 7-iodo-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester and 3-(benzyloxy)benzenethiol. MS m/z: 422 [M-Boc+H]⁺

Step 2 7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

7-(3-Benzyloxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3c]pyridine-2-carboxylic acid tert-butyl ester (1.76 g, 3.37 mmol) was dissolved in a mixture of ethyl acetate (200 ml) and methanol (100 ml). Palladium hydroxide on carbon (20% by weight, 50% wet; 200 mg, 0.1 mmol) was added and the suspension was hydrogenated at 55 psi using a Parr apparatus for 16 h. The reaction mixture was then filtered through a plug of Celite and the solvent was evaporated. The residue was purified by flash chromatography on silica gel and eluting with 50% EtOAc/hexanes to afford the title compound D01 (1.39 g). MS m/z: 332 [M-Boc+H]⁺

The following examples were prepared essentially as described immediately above.

MS m/z Stereo Preparation Chemical name [M + H]⁺ chemistry Scaffold Starting mat D01 tert-butyl 7-[(3- 432.1 racemic P01 3- hydroxyphenyl)sulfonyl]- (benzyloxy)benzenethiol 3,4,4a,9a- tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D02 tert-butyl 7-[(3- 432.1 enantiomer 1 P03 3- hydroxyphenyl)sulfonyl]- (benzyloxy)benzenethiol 3,4,4a,9a- tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D03 tert-butyl 7-[(3- 432.1 enantiomer 2 P04 3- hydroxyphenyl)sulfonyl]- (benzyloxy)benzenethiol 3,4,4a,9a- tetrahydro[1]benzofuro[2,3- c[pyridine-2(1H)-carboxylate D04 tert-butyl 7-[(3-hydroxy-2- 446.2 racemic P01 3-(benzyloxy)-2- methylphenyl)sulfony1]-3,4,4a,9a- methylbenzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D05 tert-butyl 7-[(3-hydroxy-2- 446.2 enantiomer 1 P03 3-(benzyloxy)-2- methylphenyl)sulfony1]-3,4,4a,9a- methylbenzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D06 tert-butyl 7-+(3-hydroxy-2- 446.2 enantiomer 2 P04 3-(benzyloxy)-2- methylphenyl)sulfonyl]-3,4,4a,9a- methylbenzenethiol tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D07 tert-butyl 7-[(3-hydroxy-5- 462.2 racemic P01 3-(benzyloxy)-5- methoxyphenyl )sulfonyl]- methoxybenzenethiol 3,4,4a,9a- tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D08 tert-butyl 7-[(3-hydroxy-5- 462.2 enantiomer 1 P03 3-(benzyloxy)-5- methoxyphenyl )sulfonyl]- methoxybenzenethiol 3,4,4a,9a- tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D09 tert-butyl 7-[(3-hydroxy-5- 462.2 enantiomer 2 P04 3-(benzyloxy)-5- methoxyphenyl )sulfonyl]- methoxybenzenethiol 3,4,4a,9a- tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate

D10 7-(3-Hydroxy-5-isopropoxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Step 1 7-(3-benzyloxy-5-isopropoxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester

Prepared as described for 7-(3-Fluoro-5-isopropoxy-benzenesulfonyl)-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridine hydrochloride starting from 1-(benzyloxy)-3-iodo-5-(propan-2-yloxy)benzene and tert-butyl 7-[(tripropan-2-ylsilyl)sulfanyl]-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate C02. Sulfur oxidation was performed with mCPBA as described for 6-(3-chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester.

Step 2 7-(3-Hydroxy-5-isopropoxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester D10

Synthesized as described for 7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester D01 starting from 7-(3-benzyloxy-5-isopropoxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester.

The following examples were prepared essentially as described immediately above.

MS m/z Prep Chemical name [M + H]⁺ Stereochemistry Scaffold Starting mat D10 tert-butyl 7-{[3-hydroxy-5- 490 racemic C02 1-(benzyloxy)-3-iodo- (propan-2-yloxy)phenyl]sulfonyl}- 5-(propan-2- 3,4,4a,9a- yloxy)benzene tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D11 tert-butyl 7-{[3-hydroxy-5- 490 enantiomer 1 C03 1-(benzyloxy)-3-iodo- (propan-2-yloxy)phenyl]sulfonyl}- 5-(propan-2- 3,4,4a,9a- yloxy)benzene tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D12 tert-butyl 7-{[3-hydroxy-5- 490 enantiomer 2 C04 1-(benzyloxy)-3-iodo- (propan-2-yloxy)phenyl]sulfonyl}- 5-(propan-2- 3,4,4a,9a- yloxy)benzene tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D13 tert-butyl 7-[(3-fluoro-5- 450 racemic P01 {[3-(benzyloxy)-5- hydroxyphenyl)sulfonyl]- fluorophenyl]sulfanyl}(tripropan- 3,4,4a,9a- 2-yl)silane tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D14 tert-butyl 7-[(3-fluoro-5- 450 enantiomer 1 P02 {[3-(benzyloxy)-5- hydroxyphenyl)sulfonyl]- fluorophenyl]sulfanyl}(tripropan- 3,4,4a,9a- 2-yl)silane tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate D15 tert-butyl 7-[(3-fluoro-5- 450 enantiomer 2 P03 {[3-(benzyloxy)-5- hydroxyphenyl)sulfonyl]- fluorophenyl]sulfanyl}(tripropan- 3,4,4a,9a- 2-yl)silane tetrahydro[1]benzofuro[2,3- c]pyridine-2(1H)-carboxylate 

The invention claimed is:
 1. A compound having the structure of Formula III-B

or a salt thereof, wherein: R² is selected from H, C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl; R³ and R⁴ are each H; “- - - -” is either a bond or is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl, provided that “- - - -” is absent; R⁷, R⁸, R⁹, and R¹⁰ are each H; Q is —O—; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₄-C₉)heteroaryl and C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, NR¹³CO—(C₁-C₆)alkyl, (C₄-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)haloalkoxy, (C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryloxy, and NO₂.
 2. A compound according to claim 1 or a salt thereof, wherein: W is 0; R² is H; “- - - -” is absent; R⁵ and R⁶ are each H.
 3. A compound according to claim 1 or a salt thereof, wherein: W is 0; R² is selected from (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl; “- - - -” is absent; and R⁵ and R⁶ are each H; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, NR¹³CO—(C₁-C₆)alkyl, (C₄-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)haloalkoxy, (C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryloxy, and NO₂.
 4. A compound according to claim 1 or a salt thereof, wherein: W is 0; “- - - -” is a bond; and Y is (C₄-C₉)heteroaryl optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, NR¹³CO—(C₁-C₆)alkyl, (C₄-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, (C₁-C₆)haloalkoxy, (C₂-C₉)heterocycloalkyl, (C₆-C₁₀)aryloxy, and NO₂.
 5. A compound having the structure of Formula III-C:

or a salt thereof, wherein: W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is a bond; Q is absent; and Y is selected from (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, and (C₃-C₁₀)cycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryloxy, NO₂, CO₂(C₁-C₆)alkyl, CN, NR¹³CO—(C₁-C₆)alkyl, (C₁-C₆)haloalkoxy, (C₆-C₁₀)aryl, N(R¹³)₂, and oxo.
 6. A compound having the structure of Formula III-C:

or a salt thereof, wherein: W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; Q is absent; and Y is selected from (C₆-C₁₀)aryl and (C₅-C₉)heteroaryl wherein either of the foregoing is optionally substituted with one or more substituents selected from halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, NO₂, (C₆-C₁₀)aryloxy, oxo, NR¹³CO—(C₁-C₆)alkyl, and (C₁-C₆)hydroxyalkyl.
 7. A compound having the structure of Formula III-C:

or a salt thereof, wherein: W is 0; R² is H; R³ and R⁴ are each independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl(C₁-C₆)alkoxy, (C₂-C₉)heterocycloalkyl, and (C₁-C₆)alkyl-NR¹³CO—(C₁-C₆)alkyl; or R³ and R⁴ are taken together to form a (C₃-C₉)heterocycloalkyl spirocyclic ring; R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is a bond; Z is 2; Q is absent; and Y is selected from (C₆-C₁₀)aryl optionally substituted with one or more substituents selected from halogen, (C₁-C₆)haloalkyl, and (C₁-C₆)alkoxy.
 8. A compound having the structure of Formula III-C:

or a salt thereof, wherein: W is 0; R² and one of R³ and R⁴ are taken together to form a (C₃-C₉)heterocycloalkyl ring and the other of R³ and R⁴ is H; “- - - -” is a bond; Z is 2; Q is absent; and Y is (C₆-C₁₀)aryl optionally substituted with one or more substituents selected from halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₃-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryloxy, NR¹³CO—(C₁-C₆)alkyl, (C₆-C₁₀)aryl, and NO₂.
 9. A compound having the structure of Formula III-C:

or a salt thereof, wherein: R² is selected from H, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each independently selected from H and (C₁-C₆)alkyl; Q is —O—; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, and (C₃-C₉)heteroaryl wherein any of the foregoing is optionally substituted with one or more substituents selected from halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₃-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryloxy, NR¹³CO—(C₁-C₆)alkyl, (C₆-C₁₀)aryl, and NO₂.
 10. A compound according to claim 9 or a salt thereof, wherein: W is 0; and R² is H.
 11. A compound according to claim 9 or a salt thereof, wherein: W is 0; and R² is selected from (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl.
 12. A compound having the structure of Formula III-C:

or a salt thereof, wherein: R² is selected from H and CO(C₁-C₆)alkyl; R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each H; Q is —NH—; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₃-C₉)heteroaryl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl wherein any of the foregoing may be optionally substituted with one or more substituents selected from halogen, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, (C₃-C₉)heteroaryl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryloxy, NR¹³CO—(C₁-C₆)alkyl, (C₆-C₁₀)aryl, and NO₂.
 13. A compound according to claim 12 or a salt thereof, wherein: R² is H; and Y is selected from (C₆-C₁₀)aryl, (C₃-C₉)heteroaryl, and (C₁-C₆)alkyl(C₆-C₁₀)aryl wherein any of the foregoing may be optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, halogen, and (C₁-C₆)alkoxy.
 14. A compound having the structure of Formula III-C:

or a salt thereof, wherein: W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each H; R¹³ is H or methyl; Z is 2; and Y is selected from (C₆-C₁₀)aryl, (C₁-C₆)alkyl(C₆-C₁₀)aryl, or (C₃-C₁₀)cycloalkyl wherein any of the foregoing is optionally substituted with one or more substituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and halogen.
 15. A compound according to claim 14 or a salt thereof, wherein: W is 0; R² is H; R³, R⁴, R⁷, R⁸, R⁹, R¹⁰ are each H; “- - - -” is absent; R⁵ and R⁶ are each H; Q is absent; Z is 2; and Y is NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵ are taken together to form a (C₂-C₉)heterocycloalkyl ring which is optionally substituted with one or more substituents selected from (C₆-C₁₀)aryl or (C₂-C₉)heterocycloalkyl.
 16. A composition comprising a compound according to any of claims 1 to 4 and 5 to 15, or a salt thereof, and at least one pharmaceutically acceptable excipient. 